Peroxisome proliferator activated receptor agonists

ABSTRACT

The present invention is directed to compounds represented by the following structural Formula (I), (a) R1 is selected from the group consisting of hydrogen, substituted or unsubstituted group selected from C 1 -C 8  alkyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 6  cycloalkylaryl-C 0-2 -alkyl, and —CH 2 —C(O)—R17-R18, wherein R17 is O or NH and R18 is optionally substituted benzyl; (b) R2 is selected from the group consisting of C 1 -C 6  alkyl, C 1 -C 6  alkenyl, aryl-C 0-4 -alkyl, heteroaryl-C 0-4 -alkyl, C 1 -C 4  alkyl sulfonamide, C 1 -C 4  alkyl amide, OR10 and C 3 -C 6  cycloalkyl; (c) W is O or S; (d) X is an optionally substituted C 1 -C 5  alkylene linker wherein one carbon atom of the linker may optionally be replaced with O, NH, S, and optionally two carbons together may form a double bond; (e) Y is selected from the group consisting of C, O, S, NH and a single bond; and (f) E is selected from the group consisting of C(R3) (R4)A, A, and a substituted or unsubstituted group selected from the group consisting of (CH 2 )n COOR19.

BACKGROUND OF THE INVENTION

Peroxisome Proliferator Activated Receptors (PPARs) are members of thenuclear hormone receptor super family, which are ligand-activatedtranscription factors regulating gene expression. Various subtypes ofPPARs have been discovered. These include, for example, PPARα, PPARγ andPPARδ.

PPARα, PPARγ and PPARδ receptors have been implicated in diabetesmellitus, cardiovascular disease, obesity, Syndrome X andgastrointestinal disease, such as, inflammatory bowel disease. SyndromeX is the combination of symptoms which include hyperinsulemia combinedwith hypertension, elevated body weight, elevated triglycerides andelevated LDL.

Current PPAR agonist treatment for Syndrome X relates to the use ofthiazolidinediones (TZDs) or other insulin sensitivity enhancers (ISEs).TZDs are a class of PPAR gamma agonists which have been shown toincrease the sensitivity of insulin sensitive cells. Increasing insulinsensitivity rather than the amount of insulin in the blood reduces thelikelihood of hypoglycemic coma. However, TZDs and ISEs typically havelittle effect in preventing the cardiovascular part of Syndrome X inthat their administration usually does not result in the lowering oftriglycerides and LDL-cholesterol while raising HDL-cholesterol.Furthermore, clinically significant side effects are commonly associatedwith treatment with TZDs. Therefore, a need exists for newpharmaceutical agents which affect treat or prevent cardiovasculardisease, particularly that associated with Syndrome X, while preventingor minimizing weight gain, and more preferably while improving insulinsensitivity. The present invention provides novel compounds exhibitingdesired pharmacological activity.

SUMMARY OF THE INVENTION

The present invention is directed to compounds represented by thefollowing structural formula:

Formula I

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein:

-   -   (a) R1 is selected from the group consisting of hydrogen,        substituted or unsubstituted group selected from C₁-C₈ alkyl,        aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₃-C₆        cycloalkylaryl-C₀₋₂-alkyl, and —CH₂—C(O)—R17-R18, wherein R17 is        O or NH and R18 is optionally substituted benzyl;    -   (b) R2 is H or a substituted or unsubstituted group selected        from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkenyl,        aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₁-C₄ alkyl sulfonamide,        C₁-C₄ alkyl amide, OR10 and C₃-C₆ cycloalkyl;    -   (c) W is O or S;    -   (d) X is an optionally substituted C₁-C₅ alkylene linker wherein        one carbon atom of the linker may optionally be replaced with O,        NH, S, and optionally two carbons together may form a double        bond;    -   (e) Y is selected from the group consisting of C, O, S, NH and a        single bond; and    -   (f) E is selected from the group consisting of C(R3)(R4)A, A,        and a substituted or unsubstituted group selected from the group        consisting of (CH₂)_(n)COOR19; and wherein        -   (i) n is 0, 1, 2 or 3;        -   (ii) A is an functional group selected from the group            consisting of carboxyl, C₁-C₃alkylnitrile, carboxamide,            substituted or unsubstituted sulfonamide, substituted or            unsubstituted acylsulfonamide substituted or unsubstituted            tetrazole, and substituted or unsubstituted isoxazole;        -   (iii) R3 is selected from the group consisting of H, C₁-C₅            alkyl, arylC₀-C₂alkoxy, and C₁-C₅ alkoxy, and        -   (iv) R4 is selected from the group consisting of H, halo,            and a substituted or unsubstituted group selected from C₁-C₅            alkyl, C₁-C₅ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl,            arylC₀-C₂alkoxy and phenyl; or R3 and R4 are combined to            form a C₃-C₈ cycloalkyl;        -   (v) R19 is selected from the group consisting of hydrogen,            optionally substituted arylmethyl and optionally substituted            C₁-C₄alkyl;    -   (g) R8 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, and halo;    -   (h) R9 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, halo, substituted or unsubstituted aryl,        substituted or unsubstituted aryl-C₁-C₄ alkyl, substituted or        unsubstituted heteroaryl, C₁-C₆ alkenyl, and OR10;    -   (i) R10 is independently selected from the group consisting of        hydrogen and C₁-C₄ alkyl;    -   (j) R21 is selected from the group consisting of hydrogen, ═O,        and a substituted or unsubstituted group selected from the group        consisting of C₁-C₆ alkyl, aryl, C₁-C₄ alkylaryl, and        heteroaryl;    -   (k) R22 is selected from the group consisting of hydrogen, and a        substituted or unsubstituted group selected from the group        consisting of C₁-C₆ alkyl, aryl, C₁-C₄ alkylaryl, and        heteroaryl; and    -   (l) ---- represents an optional double bond.

A compound of Formula I′

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein:

-   -   (a) R1 is selected from the group consisting of hydrogen,        substituted or unsubstituted group selected from C₁-C₈ alkyl,        aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C3-C6        cycloalkylaryl-C₀₋₂-alkyl, and —CH₂—C(O)—R17-R18, wherein R17 is        O or NH and R18 is optionally substituted benzyl;    -   (b) R2 is H or a substituted or unsubstituted group selected        from the group consisting of C₁-C₆ alkyl, C₁-C₆ alkenyl,        aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₁-C₄ alkyl sulfonamide,        C₁-C₄ alkyl amide, OR10 and C₃-C₆ cycloalkyl;    -   (c) W is O or S;    -   (d) X is an optionally substituted C₁-C₅ alkylene linker wherein        one carbon atom of the linker may be replaced with O, NH or S;    -   (e) Y is C, O, S, NH or a single bond; and    -   (f) E is selected from the group consisting of C(R3) (R4)A, A,        substituted or unsubstituted selected from the group consisting        of (CH₂)_(n) COOR19; and wherein        -   (i) n is 0, 1, 2 or 3,        -   (ii) A is an functional group selected from the group            consisting of carboxyl, C₁-C₃alkylnitrile, carboxamide,            substituted or unsubstituted sulfonamide, substituted or            unsubstituted acylsulfonamide and substituted or            unsubstituted tetrazole;        -   (iii) R3 is H, saturated or unsaturated C₁-C₅ alkyl,            arylC₀-C₂alkoxy, C₁-C₅ alkoxy, and        -   (iv) R4 is H, halo, a substituted or unsubstituted group            selected from C₁-C₅ alkyl, C₁-C₅ alkoxy, C₃-C₆ cycloalkyl,            aryl C₀-C₄ alkyl, arylC₀-C₂alkoxy and phenyl, or R3 and R4            are combined to form a C₃-C₈ cycloalkyl;        -   (v) R19 is selected from the group consisting of hydrogen,            optionally substituted arylmethyl and optionally substituted            C₁-C₄alkyl;    -   (g) R8 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, and halo;    -   (h) R9 is selected from the group consisting of hydrogen, C₁-C₄        alkyl, C₁-C₄ alkylenyl, halo, substituted or unsubstituted aryl,        substituted or unsubstituted aryl-C₁-C₄ alkyl, substituted or        unsubstituted heteroaryl, C₁-C₆ alkenyl, and OR10;    -   (i) R10 is independently selected from the group consisting of        hydrogen and C₁-C₄ alkyl;    -   (j) R21 is selected from the group consisting of hydrogen, ═O,        and a substituted or unsubstituted group selected from the group        consisting of C₁-C₆ alkyl, aryl, C₁-C₄ alkylaryl, and        heteroaryl;    -   (k) R22 is selected from the group consisting of hydrogen, and a        substituted or unsubstituted group selected from the group        consisting of C₁-C₆ alkyl, aryl, C₁-C₄ alkylaryl, and        heteroaryl; and    -   (1)----represents an optional double bond.

An additional embodiment is a compound and pharmaceutically acceptablesalts, solvates and hydrates of Structural Formula II:

An additional embodiment is a compound and pharmaceutically acceptablesalts, solvates and hydrates of Structural Formula III:

Another embodiment of this invention is a compound of Formula IVrepresented by the following structure:

and salts, solvates and hydrates thereof.

One preferred embodiment of this invention is a compound selected fromthe group consisting of2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid and2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionicacid.

In another feature of this invention, a compound claimed herein isradiolabeled.

In one embodiment, the present invention also relates to pharmaceuticalcompositions which comprising at least one compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, hydrate orprodrug thereof, and a pharmaceutically acceptable carrier.

In another embodiment, the present invention relates to a method ofmodulating one or more PPAR receptor(s) by contacting the receptor withat least one compound represented by Structural Formula I, andpharmaceutically acceptable salts, solvates and hydrates thereof.

In another embodiment, the present invention relates to a method ofselectively modulating a PPAR receptor by contacting the receptor withat least one compound represented by Structural Formula I, andpharmaceutically acceptable salts, solvates and hydrates thereof.Another embodiment of this invention is preferentially modulating onePPAR receptor and additionally modulating a second, different, PPARreceptor to provide desired dual agonism.

In a further embodiment, the present invention relates to a method ofmaking a compound represented by Structural Formula I.

The compounds of the present invention and pharmaceutically acceptablesalts, solvates and hydrates thereof are believed to be effective intreating and preventing Syndrome X, Type II diabetes, hyperglycemia,hyperlipidemia, obesity, coagaulopathy, hypertension, atherosclerosis,and other disorders related to Syndrome X and cardiovascular diseases.In addition, the compounds exhibit fewer side effects than compoundscurrently used to treat these conditions. Further, compounds of thisinvention can be useful for lowering fibrinogen, increasing HDL levels,treating renal disease, controlling desirable weight, treatingdemyelinating diseases, treating certain viral infections, and treatingliver disease.

DETAILED DESCRIPTION OF THE INVENTION

The terms used to describe the instant invention have the followingmeanings herein.

As used herein, alkyl groups include straight chained or branchedhydrocarbons, which are completely saturated. Said branched hydrocarbonmay be primary, secondary, tertiary, or quaternary, as appropriate.

As used herein, alkylene linker is a C₁-C₅ straight or branched chainhydrocarbon group. However, the term “alkylene linker wherein one carbonof the linker may optionally be replaced with O, NH, S, and optionallytwo carbons together may form a double bond” refers to an alkylenelinking having an O, NH or S in the link. Alkylene linkers having twocarbons together forming a double bond means for example, —CH—CHCH₂—,—CH₂CHCH—, —CH₂CH₂CHCH—, and the like. For example, but not limited to,—CH₂CH₂O—, —CH₂CH₂NH—, CH₂CH₂S—, —CH₂OCH₂—, —OCH₂CH₂—, and the like.

Cycloalkyl groups, as used herein, include cyclic hydrocarbons, whichare partially or completely saturated.

As used herein, aryl groups include carbocyclic aromatic ring systems(e.g. phenyl), fused polycyclic aromatic ring systems (e.g. naphthyl andanthracenyl) and aromatic ring systems fused to carbocyclic non-aromaticring systems (e.g., 1,2,3,4-tetrahydronaphthyl and benzodioxyl).

Heterocyclic group, as used herein, is a ring system having at least oneheteroatom such as nitrogen, sulfur or oxygen. Heterocyclic groupsinclude benzofuranyl, benzothiazolyl, benzothienyl, isoquinolyl,isoxazolyl, morpholino, oxadiazolyl, pyridyl, pyrimidinyl, pyrrolyl,quinolyl, tetrahydropyranyl and thienyl.

Heteroaryl, as used herein is an aromatic ring system, fused polycyclicaromatic ring systems and aromatic ring systems fused to non-aromaticring systems wherein at least one carbon atom is replaced with aheteroatom such as nitrogen, sulfur or oxygen. It may be preferred thatheteroaryl contains from 1-3 heteroatoms. It may be preferred thatheteroaryl contains 1-2 nitrogen atoms. One heteroaryl group that may bedesired is

Another heteroaryl group that may be desired is:

The term “arylalky”, “arylmethyl”, “arylC₀-C₂alkoxy” and “aryloxy” eachrepresent a substituent in which the aryl group is linked to the parentmolecule via the alkyl, methyl, and oxy, respectively. Additionally,when the phrase “arylC₀-C₂alkoxy” is C₀ alkoxy, this means that the arylis linked to the parent molecule via an oxy group.

Examples of R1, R5, E, R19 and R9 suitable substituents when said R1, E,R5, R19 or R9 are at least one or more independently selected from thegroup consisting of C₁-C₈alkyl, C₁-C₄ alkyl, aryl, arylmethyl,(CH₂)_(n)COOR19, C₁-C₆ alkenyl, thio-C₁-C₄alkyl, thioaryl,C₁-C₄alkoxyaryl, C₁-C₄alkoxy C₁-C₄alkyl, aminoaryl, aminoC₁-C₄alkyl,aryl-Co ₄alkyl, heteroarylC₀₋₄alkyl, heterocyclic, —CH₂—C(O)—R17-R18,(C₃-C₆)cycloalkylaryl-C₀₋₂-alkyl and cycloalkyl, then suitablesubstituted groups include, for example, C₁-C₅ alkyl, C₁-C₅ alkoxy,C₀-C₅ haloalkyl, C₁-C₅ trihaloalkyl, C₁-C₅ trihaloalkoxy, C₁-C₅haloalkoxy, nitro, cyano, CHO, ═O, hydroxyl, C₁-C₄ alkanoic acid,phenyl, aryloxy, SO₂R7, SR7, benzyloxy, alkylcarboxamido or COOH. R7 isan alkyl or a haloalkyl. When R1, R5, E, R19 or R9 is substituted, it ispreferred that there are from 1-3 substitutions on said R1, R5, E, R19or R9 group. An especially preferred trihaloalkyl group is trifluoroC₁-C₅ alkyl.

Examples of suitable substituents for an “optionally substituted C₂-C₅alkylene linker,” include one or more independently selected from thegroup consisting of C₁-C₆alkyl, oxo, substituted or unsubstitutedarylC₀-C₃alkyl, C₁-C₃alkoxy, hydroxy, C₃-C₆cycloalkyl and halo. When thealkylene linker is substituted, it is preferred that there are from oneto three independent substitutions.

Examples of suitable substituents for a substituted C₁-C₃ alkylene,include one or more independently selected from C₁-C₆alkyl, oxo, arylC₀-C₃alkyl, C₁-C₃alkoxy, hydroxy, and halo. When the alkylene issubstituted it is preferred that there are from 1-3 independentsubstitutions.

Suitable substituents for substituted R2 groups wherein R2 isC₁-C₆alkyl, C₁-C₆alkenyl, arylC₀-C₄alkyl, arylC₀-C₄alkyl, C₁-C₄ alkylsulfonamide, C₁-C₄ alkyl amide, OR10, or C₃-C₆cycloalkyl, include forexample, one or more independently selected from the group consisting ofOH, alkoxy, haloalkyl, amino, COOH, heteroaryl-O—, heteroaryl-C(O)—,alkyl-O—, alkyl-C(O)—, C₃-C₆ cycloalkyl, aryl-O—, aryl-C(O)—,heteroaryl, aryl, heterocycloalkyl, heterocycloalkyl-O—, andheterocycloalkyl-C(O)—. When R2 is substituted it is preferred thatthere are from 1-3 independent substitutions on the R2 group.

Examples of suitable substituents for A groups, wherein the A is asulfonamide, include one or more independently selected from C₁-C₄alkyl, C₁-C₄ haloalkyl, substituted or unsubstituted heteroaryl, orsubstituted or unsubstituted aryl. When the A group is substituted, itis preferred that there are from 1-3 independent substitutions on the Agroup.

Examples of suitable substituents for A groups, wherein A isacylsulfonamide and tetrazole include, for example, one or moreindependently selected from C₁-C₄ alkyl, C₁-C₄ haloalkyl, substituted orunsubstituted heteroaryl, or substituted or unsubstituted aryl.

Suitable substituents for R4 wherein R4 is C₁-C₅ alkyl, C₁-C₅alkoxy,C₁-C₆cycloalkyl, arylC₀-C₄alkyl, arylC₀-C₂alkoxy or phenyl, include, forexample halo, phenyl, C₁-C₄ alkoxy, hydroxy, and arylC₀-C₂alkoxy. WhenR4 is substituted, it is preferred that there are from 1-4 independentlyselected substitutions on the R4 group.

Preferably, for the compounds of the present invention, represented byStructural Formula I, and with their respective pharmaceuticalcompositions, W is an oxygen.

The compounds of Structural Formula I may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof Structural Formula I contain one chiral center, the compounds existin two enantiomeric forms and the present invention includes bothenantiomers and mixtures of enantiomers, such as racemic mixtures. Theenantiomers may be resolved by methods known to those skilled in theart, for example by formation of diastereoisomeric salts which may beseparated, for example, by crystallization; formation ofdiastereoisomeric derivatives or complexes which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective reaction of one enantiomer with an enantiomer-specificreagent, for example enzymatic esterification; or gas-liquid or liquidchromatography in a chiral environment, for example on a chiral supportfor example silica with a bound chiral ligand or in the presence of achiral solvent. It will be appreciated that where the desired enantiomeris converted into another chemical entity by one of the separationprocedures described above, a further step is required to liberate thedesired enantiomeric form. Alternatively, specific enantiomers may besynthesized by asymmetric synthesis using optically active reagents,substrates, catalysts or solvents, or by converting one enantiomer intothe other by asymmetric transformation.

When a compound represented by Structural Formula I has more than onechiral substituent it may exist in diastereoisomeric forms. Thediastereoisomeric pairs may be separated by methods known to thoseskilled in the art, for example chromatography or crystallization andthe individual enantiomers within each pair may be separated asdescribed above. The present invention includes each diastereoisomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I may exist in zwitterionic formand the present invention includes each zwitterionic form of compoundsof Structural Formula I and mixtures thereof.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof. “Pharmaceutically-acceptablesalt” refers to salts of the compounds of the Structural Formula I whichare substantially non-toxic to mammals. Typical pharmaceuticallyacceptable salts include those salts prepared by reaction of thecompounds of the present invention with a mineral or organic acid or anorganic or inorganic base. Such salts are known as base addition salts,respectively. It should be recognized that the particular counterionforming a part of any salt of this invention is not of a criticalnature, so long as the salt as a whole is pharmaceutically acceptableand as long as the counterion does not contribute undesired qualities tothe salt as a whole.

By virtue of its acidic moiety, a compound of Structural Formula I formssalts with pharmaceutically acceptable bases. Some examples of baseaddition salts include metal salts such as aluminum; alkali metal saltssuch as lithium, sodium or potassium; and alkaline earth metal saltssuch as calcium and magnesium; and ammonium or substituted ammoniumsalts. Examples of substituted ammonium salts include, for instance,those with lower alkylamines such as trimethylamine, triethylamine;hydroxyalkylamines such as 2-hydroxyethylamine,bis-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-amine,cycloalkylamines such as bicyclohexylamine or dibenzylpiperidine,N-benzyl-β-phenethylamine, dehydroabietylamine,N,N′-bisdehydro-abietylamine, glucamine, N-methylglucamine; bases of thepyridine type such as pyridine, collidine, quinine or quinoline; andsalts of basic amino acids such as lysine and arginine.

Examples of inorganic bases include, without limitation, sodiumhydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calciumcarbonate, and the like.

Compounds of Structural Formula I, which are substituted with a basicgroup, may exist as salts with pharmaceutically acceptable acids. Thepresent invention includes such salts. Examples of such salts includehydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, tartrates [e.g. (+)-tartrates,(−)-tartrates or mixtures thereof including racemic mixtures],succinates, benzoates and salts with amino acids such as glutamic acid.

These salts may be prepared by methods known to those skilled in theart.

Certain compounds of Structural Formula I and their salts may also existin the form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

In addition, it is generally not desirable to formulate pharmaceuticalscontaining substantial amounts of organic solvent (e.g., ethyl acetate)due to potential solvent toxicity to the recipient thereof and changesin potency of the pharmaceutical as a function of the solvent. Inaddition, from a manufacturing perspective, it is also generally lessdesirable to prepare non-crystalline materials whenever said preparationinvolves a collection of the final product via filtration. Suchfiltrations are often more difficult to perform when the materialcollected is non-crystalline. Moreover, it is also generally lessdesirable, from a manufacturing perspective, to formulatepharmaceuticals containing substantial amounts of water (hydrates)because the level of hydration will typically be some function of therelative humidity at which the pharmaceutical is produced and stored. Inother words, potency variability is typically more problematic with ahydrate relative to its anhydrous form. The present invention provides adesired crystalline form.

Prodrugs are compounds of the present invention, which have chemicallyor metabolically cleavable groups and become by solvolysis or underphysiological conditions the compounds of the invention which arepharmaceutically active in vivo. Prodrugs include acid derivatives wellknown to practitioners of the art, such as, for example, esters preparedby reaction of the parent acidic compound with a suitable alcohol, oramides prepared by reaction of the parent acid compound with a suitableamine. Simple aliphatic or aromatic esters derived from acidic groupspendent on the compounds of this invention are preferred prodrugs. Insome cases it is desirable to prepare double ester type prodrugs such as(acyloxy) alkyl esters or ((alkoxycarbonyl)oxy)alkyl esters.Particularly preferred esters as prodrugs are methyl, ethyl, propyl,isopropyl, n-butyl, isobutyl, tert-butyl, morpholinoethyl, andN,N-diethylglycolamido.

Methyl ester prodrugs may be prepared by reaction of the acid form of acompound of Formula I in a medium such as methanol with an acid or baseesterification catalyst (e.g., NaOH, H₂SO₄). Ethyl ester prodrugs areprepared in similar fashion using ethanol in place of methanol.

Morpholinylethyl ester prodrugs may be prepared by reaction of thesodium salt of a compound of Structural Formula I (in a medium such asdimethylformamide) 4-(2-chloroethyl)morphine hydrochloride (availablefrom Aldrich Chemical Co., Milwaukee, Wis. USA, Item No. C4,220-3).

The term, “active ingredient” means the compounds generically describedby Structural Formula I as well as the salts, solvates, and prodrugs ofsuch compounds. The term “pharmaceutically acceptable” means that thecarrier, diluent, excipients and salt must be compatible with the otheringredients of the composition, and not deleterious to the recipientthereof. Pharmaceutical compositions of the present invention areprepared by procedures known in the art using well-known and readilyavailable ingredients. “Preventing” refers to reducing the likelihoodthat the recipient will incur or develop any of the pathologicalconditions described herein. “Treating” refers to mediating a disease orcondition and preventing, or mitigating, its further progression orameliorate the symptoms associated with the disease or condition.“Pharmaceutically-effective amount” means that amount of a compound, orof its salt, solvate, hydrate or prodrug thereof, that will elicit thebiological or medical response of a tissue, system, or mammal. Such anamount can be administered prophylactically to a patient thought to besusceptible to development of a disease or condition. Such amount whenadministered prophylactically to a patient can also be effective toprevent or lessen the severity of the PPAR mediated condition. Such anamount is intended to include an amount which is sufficient to modulatea PPAR receptor or to prevent or mediate a disease or condition.Conditions prevented or treated by PPAR receptors include, but are notlimited to, diabetes mellitus, cardiovascular disease, Syndrome X,obesity and gastrointestinal disease.

A “mammal” is an individual animal that is a member of the taxonomicclass Mammalia. The class Mammalia includes humans, monkeys,chimpanzees, gorillas, cattle, swine, horses, sheep, dogs, cats, mice,and rats.

Administration to a human is most preferred. The compounds andcompositions of the present invention can be useful for the treatmentand/or prophylaxis of cardiovascular disease, for raising serum HDLcholesterol levels, for lowering serum triglyceride levels and for lowerserum LDL cholesterol levels. Elevated triglyceride and LDL levels, andlow HDL levels, are considered risk factors for the development of heartdisease, stroke, and circulatory system disorders and diseases.

The compounds and compositions of the present invention can also beuseful for treating and/or preventing obesity.

Further, these compounds and compositions can be useful for thetreatment and/or prophylaxis of non-insulin dependent diabetes mellitus(NIDDM) with reduced or no body weight gains by the patients.Furthermore, the compounds and compositions of the present invention canbe useful to treat or prevent acute or transient disorders in insulinsensitivity, such as sometimes occur following surgery, trauma,myocardial infarction, and the like. The physician of ordinary skill canidentify humans who will benefit from administration of the compoundsand compositions of the present invention.

The present invention further provides a method for the treatment and/orprophylaxis of hyperglycemia in a human or non-human mammal whichcomprises administering an effective, non-toxic amount of a compound ofthe general formula (I), or a tautomeric form thereof and/or apharmaceutically acceptable salt thereof and/or a pharmaceuticallyacceptable solvate thereof to a hyperglycemic human or non-human mammalin need thereof.

They are useful as therapeutic substances in preventing or treatingSyndrome X, diabetes mellitus and related endocrine and cardiovasculardisorders and diseases in human or non-human animals.

The invention also relates to the use of a compound of Formula I asdescribed above, for the manufacture of a medicament for treating a PPARreceptor mediated condition.

A therapeutically effective amount of a compound of Structural Formula Ican be used for the preparation of a medicament useful for treatingSyndrome X, diabetes, treating obesity, lowering tryglyceride levels,lowering serum LDL levels, raising the plasma level of high densitylipoprotein, and for treating, preventing or reducing the risk ofdeveloping atherosclerosis, and for preventing or reducing the risk ofhaving a first or subsequent atherosclerotic disease event in mammals,particularly in humans. In general, a therapeutically effective amountof a compound of the present invention typically reduces serumtriglyceride levels of a patient by about 20% or more, and increasesserum HDL levels in a patient. Preferably, HDL levels will be increasedby about 30% or more. In addition, a therapeutically effective amount ofa compound, used to prevent or treat NIDDM, typically reduces serumglucose levels, or more specifically HbAlc, of a patient by about 0.7%or more.

Advantageously, compositions containing the compound of StructuralFormula I and/or the salts thereof may be provided in dosage unit form.Preferably each dosage unit contain from about 1 to about 500 mg ofactive ingredient. Although it will, of course, readily be understoodthat the amount of the compound or compounds of Structural Formula Iactually to be administered will be determined by a physician, in thelight of all the relevant circumstances.

When used herein Syndrome X includes pre-diabetic insulin resistancesyndrome and the resulting complications thereof, insulin resistance,non-insulin dependent diabetes, dyslipidemia, hyperglycemia obesity,coagulopathy, hypertension and other complications associated withdiabetes. The methods and treatments mentioned herein include the aboveand encompass the treatment and/or prophylaxis of any one of or anycombination of the following: pre-diabetic insulin resistance syndrome,the resulting complications thereof, insulin resistance, Type II ornon-insulin dependent diabetes, dyslipidemia, hyperglycemia, obesity andthe complications associated with diabetes including cardiovasculardisease, especially atherosclerosis.

The compounds of the present invention can be useful for treating PPARmediated conditions and for use as research tools. Certain compounds andconditions within the scope of this invention are preferred. Thefollowing conditions, invention embodiments, and compoundcharacteristics listed in tabular form may be independently combined toproduce a variety of preferred compounds and treatment conditions. Thefollowing list of embodiments of this invention is not intended to limitthe scope of this invention in any way.

Some preferred characteristics of compounds of Formula I are:

-   -   (a) R3 is methyl;    -   (b) R3 is arylC₀-C₂alkoxy;    -   (c) R4 is arylC₀-C₂alkoxy;    -   (d) R4 is arylalkyl;    -   (e) R3 and R4 are each C₁-C₆ alkyl;    -   (f) A is carboxyl;    -   (g) W is 0;    -   (h) W is S;    -   (i) X is —CH₂CH₂CH₂—;    -   (j) X is —CH₂CH₂O—;    -   (k) R9 is methyl;    -   (l) R9 is benzyl;    -   (m) R9 is heteroarylalkyl;    -   (n) R8 is hydrogen;    -   (O) R10 is methyl    -   (p) Y is CH₂;    -   (q) Y is 0;    -   (r) R21 is ═O;    -   (s) R21 is H;    -   (t) R22 is H;    -   (u) R1 is arylalkyl;    -   (v) R1 is substituted arylalkyl;    -   (w) R2 is methyl;    -   (x) R2 is H;    -   (y) E is C(R3) (R4)A;    -   (z) A is tetrazole;    -   (aa) A is acylsulfonamide;    -   (bb) R21 is arylalkyl;    -   (cc) R1 arylalkyl is substituted by CF₃;    -   (dd) Aryl is a phenyl group;    -   (ee) Heteroaryl group contains a N;    -   (ff) “----” represents a double bond, as shown by Formula I        herein;    -   (gg) A compound of Formula I that selectively modulates an alpha        receptor;    -   (hh) A compound of Formula I that is a PPAR coagaonist that        modulates an alpha receptor and a gamma receptor; and    -   (ii) A compound of Formula I for use in the treatment of        cardiovascular disease.    -   (jj) A compound of Formula I for use in the treatment of Type II        diabetes and/or Syndrome X.

The compositions are formulated and administered in the same generalmanner as detailed herein. The compounds of the instant invention may beused effectively alone or in combination with one or more additionalactive agents depending on the desired target therapy. Combinationtherapy includes administration of a single pharmaceutical dosagecomposition which contains a compound of Structural Formula I and one ormore additional active agents, as well as administration of a compoundof Structural Formula I and each active agent in its own separatepharmaceutical dosage formulation. For example, a compound of StructuralFormula I or thereof and an insulin secretogogue such as biguanides,thiazolidinediones, sulfonylureas, insulin, or α-glucosidose inhibitorscan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, a compound of Structural Formula I and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

An example of combination treatment or prevention of atherosclerosis maybe wherein a compound of Structural Formula I or salts thereof isadministered in combination with one or more of the following activeagents: antihyperlipidemic agents; plasma HDL-raising agents;antihypercholesterolemic agents, fibrates, vitamins, aspirin, and thelike. As noted above, the compounds of Structural Formula I can beadministered in combination with more than one additional active agent.

Another example of combination therapy can be seen in treating diabetesand related disorders wherein the compounds of Structural Formula I,salts thereof can be effectively used in combination with, for example,sulfonylureas, biguanides, thiazolidinediones, α-glucosidase inhibitors,other insulin secretogogues, insulin as well as the active agentsdiscussed above for treating atherosclerosis.

The compounds of the present invention, and the pharmaceuticallyacceptable salts, solvates and hydrates thereof, have valuablepharmacological properties and can be used in pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof the present invention, or pharmaceutically acceptable salts, estersor prodrugs thereof, in combination with one or more pharmaceuticallyacceptable excipients. Excipients are inert substances such as, withoutlimitation carriers, diluents, fillers, flavoring agents, sweeteners,lubricants, solubilizers, suspending agents, wetting agents, binders,disintegrating agents, encapsulating material and other conventionaladjuvants. Proper formulation is dependent upon the route ofadministration chosen. Pharmaceutical compositions typically containfrom about 1 to about 99 weight percent of the active ingredient whichis a compound of the present invention.

Preferably, the pharmaceutical formulation is in unit dosage form. A“unit dosage form” is a physically discrete unit containing a unit dose,suitable for administration in human subjects or other mammals. Forexample, a unit dosage form can be a capsule or tablet, or a number ofcapsules or tablets. A “unit dose” is a predetermined quantity of theactive compound of the present invention, calculated to produce thedesired therapeutic effect, in association with one or morepharmaceutically-acceptable excipients. The quantity of activeingredient in a unit dose may be varied or adjusted from about 0.1 toabout 1000 milligrams or more according to the particular treatmentinvolved.

The dosage regimen utilizing the compounds of the present invention isselected by one of ordinary skill in the medical or veterinary arts, inview of a variety of factors, including, without limitation, thespecies, age, weight, sex, and medical condition of the recipient, theseverity of the condition to be treated, the route of administration,the level of metabolic and excretory function of the recipient, thedosage form employed, the particular compound and salt thereof employed,and the like.

Preferably, the compounds of the present invention are administered in asingle daily dose, or the total daily dose may be administered individed doses, two, three, or more times per day. Where delivery is viatransdermal forms, of course, administration is continuous.

Suitable routes of administration of pharmaceutical compositions of thepresent invention include, for example, oral, eyedrop, rectal,transmucosal, topical, or intestinal administration; parenteral delivery(bolus or infusion), including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraven-tricular, intravenous, intraperitoneal, intranasal, orintraocular injections. The compounds of the invention can also beadministered in a targeted drug delivery system, such as, for example,in a liposome coated with endothelial cell-specific antibody.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, powders, sachets,granules, dragees, capsules, liquids, elixers, tinctures, gels,emulsions, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores.

For oral administration in the form of a tablet or capsule, the activeingredient may be combined with an oral, non-toxic,pharmaceutically-acceptable carrier, such as, without limitation,lactose, starch, sucrose, glucose, methyl cellulose, calcium carbonate,calcium phosphate, calcium sulfate, sodium carbonate, mannitol,sorbitol, and the like; together with, optionally, disintegratingagents, such as, without limitation, cross-linked polyvinyl pyrrolidone,maize, starch, methyl cellulose, agar, bentonite, xanthan gum, alginicacid, or a salt thereof such as sodium alginate, and the like; and,optionally, binding agents, for example, without limitation, gelatin,acacia, natural sugars, beta-lactose, corn sweeteners, natural andsynthetic gums, acacia, tragacanth, sodium alginate,carboxymethyl-cellulose, polyethylene glycol, waxes, and the like; and,optionally, lubricating agents, for example, without limitation,magnesium stearate, sodium stearate, stearic acid, sodium oleate, sodiumbenzoate, sodium acetate, sodium chloride, talc, and the like. When adosage unit form is a capsule, it may contain, in addition to materialsof the above type, a liquid carrier such as a fatty oil.

Solid form formulations include powders, tablets and capsules. A solidcarrier can be one or more substance which may also act as flavoringagents, lubricants, solubilisers, suspending agents, binders, tabletdisintegrating agents and encapsulating material.

In powders, the carrier is a finely divided solid which is in admixturewith the finely divided active ingredient. In tablets, the activeingredient is mixed with a carrier having the necessary bindingproperties in suitable proportions and compacted in the shape and sizedesired.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Sterile liquid formulations include suspensions, emulsions, syrups, andelixirs. The active ingredient can be dissolved or suspended in apharmaceutically acceptable carrier, such as sterile water, sterileorganic solvent, or a mixture of both sterile water and sterile organicsolvent.

The active ingredient can also be dissolved in a suitable organicsolvent, for example, aqueous propylene glycol. Other compositions canbe made by dispersing the finely divided active ingredient in aqueousstarch or sodium carboxymethyl cellulose solution or in a suitable oil.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

All formulations for oral administration should be in dosages suitablefor such administration. Particularly suitable compositions for oraladministration are unit dosage forms such as tablets and capsules.

For parental administration the compounds of the present invention, orsalts thereof, can be combined with sterile aqueous or organic media toform injectable solutions or suspensions. Formulations for injection maybe presented in unit dosage form, such as in ampoules or in multi-dosecontainers, with an added preservative. The compositions may take suchforms as suspensions, solutions or emulsions in oily or aqueousvehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The pharmaceutical forms suitablefor injectable use include sterile aqueous solutions or dispersions andsterile powders for the extemporaneous preparation of sterile injectablesolutions or dispersions. In all cases, the form must be sterile andmust be fluid to the extent that each syringability exists. It must bestable under the conditions of manufacture and storage and must bepreserved against any contamination. The carrier can be solvent ordispersion medium containing, for example, water, preferably inphysiologically compatible buffers such as Hanks' solution, Ringer'ssolution, or physiological saline buffer, ethanol, polyol (e.g.glycerol, propylene glycol and liquid polyethylene glycol), propyleneglycol and liquid polyethylene glycol), suitable mixtures thereof, andvegetable oils. Under ordinary conditions of storage and use, thesepreparations contain a preservative to prevent the growth ofmicroorganisms.

The injectable solutions prepared in this manner can then beadministered intravenously, intraperitoneally, subcutaneously, orintramuscularly, with intramuscular administration being preferred inhumans.

For transmucosal administration, penetrants appropriate to the barrier,to be permeated are used in the formulation. Such penetrants aregenerally known in the art. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in a conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of a dry powderinhaler, or an aerosol spray presentation from pressurized packs or anebuliser, with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of pressurized aerosol the dosage unit may be determined byproviding a valve to deliver a metered amount. Capsules and cartridgesof gelatin for use in an inhaler or insufflator may be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

Pharmaceutical compositions of the present invention can be manufacturedin a manner that is itself known, e.g., by means of conventional mixing,dissolving, granulating, dragee-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes.

In making the compositions of the present invention, the activeingredient will usually be admixed with a carrier, or diluted by acarrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, lyophilized solid or paste, semi-solid, orliquid material which acts as a vehicle, or can be in the form oftablets, pills, powders, lozenges, elixirs, suspensions, emulsions,solutions, syrups, aerosols (as a solid or in a liquid medium), orointment, containing, for example, up to 10% by weight of the activecompound. The compounds of the present invention are preferablyformulated prior to administration.

The following pharmaceutical formulations 1 through 8 are illustrativeonly and are not intended to limit the scope of the invention in anyway. “Active Ingredient”, refers to a compound according to StructuralFormula I or salts thereof.

Formulation 1

Hard gelatin capsules are prepared using the following ingredients:Quantity (mg/capsule) Active Ingredient 250 Starch, dried 200 Magnesiumstearate  10 Total 460 mg

Formulation 2

A tablet is prepared using the ingredients below: Quantity (mg/tablet)Active Ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide,fumed  10 Stearic acid  5 Total 665 mg

The components are blended and compressed to form tablets each weighing665 mg.

Formulation 3

An aerosol solution is prepared containing the following components:Weight Active Ingredient  0.25 Ethanol  25.75 Propellant 22(Chlorodifluoromethane)  74.00 Total 100.00

The Active Ingredient is mixed with ethanol and the mixture added to aportion of the propellant 22, cooled to 30° C. and transferred to afilling device. The required amount is then fed to a stainless steelcontainer and diluted with the remainder of the propellant. The valveunits are then fitted to the container.

Formulation 4

Tablets, each containing 60 mg of Active ingredient, are made asfollows: Active Ingredient   60 mg Starch   45 mg Microcrystallinecellulose   35 mg Polyvinylpyrrolidone (as 10% solution in water)   4 mgSodium carboxymethyl starch  4.5 mg Magnesium stearate  0.5 mg Talc   1mg Total  150 mg

The Active Ingredient, starch and cellulose are passed through a No. 45mesh U.S. sieve and mixed thoroughly. The aqueous solution containingpolyvinylpyrrolidone is mixed with the resultant powder, and the mixturethen is passed through a No. 14 mesh U.S. sieve. The granules soproduced are dried at 50° C. and passed through a No. 18 mesh U.S.sieve. The sodium carboxymethyl starch, magnesium stearate and talc,previously passed through a No. 60 mesh U.S. sieve, are then added tothe granules which, after mixing, are compressed on a tablet machine toyield tablets each weighing 150 mg.

Formulation 5

Capsules, each containing 80 mg of Active Ingredient, are made asfollows: Active Ingredient  80 mg Starch  59 mg Microcrystallinecellulose  59 mg Magnesium stearate  2 mg Total 200 mg

The Active Ingredient, cellulose, starch, and magnesium stearate areblended, passed through a No. 45 mesh U.S. sieve, and filled into hardgelatin capsules in 200 mg quantities.

In yet another embodiment of the compounds of the present invention, thecompound is radiolabelled, such as with carbon-14, or tritiated. Saidradiolabelled or tritiated compounds are useful as reference standardsfor in vitro assays to identify new PPARα and or PPARδ agonists.

SYNTHESIS

Compounds of the present invention have been formed as specificallydescribed in the examples. Further, many compounds were prepared as moregenerally as shown in the following schematic. Alternative synthesismethods may also be effective and known to the skilled artisan.

The process as shown by the following scheme may be used to make certaincompounds of this invention:

The reaction of intermediate A with an excess of trifluoroacetic acid atambient temperature in methylene chloride overnight produces the fibrateacid (see Scheme immediately above). The fibrate acid was washed untilonly traces of trifluoroacetic acid were present in the crude product,and then the fibrate acid is used to prepare compounds claimed here.

To the solution of the α-hydroxy ester (0.04 g, (0.08 mmol) in DMF, isadded silver oxide (0.28 g, 1.2 mmol) and ethyl iodide (0.07 mL, 1.0mmol). The mixture is stirred at room temperature for 16 h, and thenstirred at 50° C. for another 16 h. Filtered, the filtrate is washedwith water and extracted with EtOAc. The organic layer is evaporated,dried (MgSO₄), concentrated and chromatographed (silica gel;hexane/EtOAc, 1:1 to 0:1). An oil is isolated as the ethyl ester (25 mg,59%). MS (ESI) m/z 537 (M+H)⁺. The ester is then hydrolyzed with 5.0NNaOH in methanol at 60° C. for 4 h. Acidified with conc.HCl, extractedwith EtOAc, the organic layer is dried (MgSO₄) and concentrated toafford the title acid. MS (ESI) m/z 509 (M+H)⁺. Other members of thisfamily could be prepared using the same method and the appropriate alkyliodide.

To a mixture of 54 mg (0.13 mmol) of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester in 2 mL of dry DMF at 0° C. under an atmosphere ofnitrogen, 10 mg of NaH (0.253 mmol) is added. The resulting solution isallowed to stand at r.t. for 20 min. Then 0.26 mmol of the appropriatearyl halide is added and resulting mixture is allowed to stand at r.t.for 3 h. The reaction mixture is diluted with ethyl acetate and 1N HCl.The organic layer is then washed with 1N HCl (2×10 mL), brine (2×10 mL),dried over Na₂SO₄, filtered and concentrated under vacuum. The resultingesters were purified by flash chromatography, and could be used asstarting materials in subsequent coupling reactions, or hydrolized tofinal compounds: To hydrolize, the ester is dissolved in 2 mL of MeOHand 0.3 mL of 5N NaOH, and the mixture is heated to 50° C. for 2 h. Theorganic solvent is then removed under vacuum and the residue isdissolved in CH₂Cl₂ and 1N HCl. Aqueous layer is washed with CH₂Cl₂(2×10 mL). Combined organic layer is dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude material is purified by MS/LC orflash chromatography to give the final products.

To the aryl bromide (or chloride) (0.07 mmol) in 1,4 dioxane (2 mL) in aN₂ purged sealed tube, is added aryl boronic acid (0.12 mmol), Cesiumfluoride (0.18 mmol) and tetrakis(triphenylphosphine) Pd (O) (0.007mmol). The reaction mixture is stirred at 110° C. for 2 h. Cooled,diluted with EtOAc and quenched with water. The organic layer is dried(MgSO₄), filtered and concentrated. The residue is then hydrolyzed with5.0 N NaOH in methanol at 60° C. for 2 h. Acidified, extracted withEtOAc, the crude acid is chromatographed (silica gel; EtOAc/MeOH, 10:0to 10:1).

General Example D: Buchwald Couplings

General Procedure:

The phenyl bromide (0.04 g, 0.067 mmol), phenol (12 mg, 0.13 mmol),Cs₂CO₃ (33 mg, 0.1 mmol), (CuOTf)₂·PhH (2 mg), ethyl acetate (0.0033mmol, 5.0 mol %) and toluene were added to a sealed tube which is purgedwith nitrogen. The mixture is heated to 100° C. until the phenyl bromideis consumed as determined by LC-MS. Cooled, diluted with ethyl acetateand washed with H₂O. The organic layer is dried (MgSO₄), concentrated toafford the crude product. The crude ester is then hydrolyzed with 5.0NNaOH in MeOH at 60° C. for 2 h. Acidified, extracted with ethyl acetate,the organic layer is dried (MgSO₄), concentrated and chromatographed(silica gel; EtOAc/MeOH, 10:0 to 10:1) to afford the pure acid.

2-Isopropoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid methyl ester

3-(4-Hydroxy-phenyl)-2-isopropoxy-propionic acid methyl ester (1.7 g,7.3 mmol), Toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester(3.4 g, 8.0 mmol), and Cs₂CO₃ (3.6 g, 11 mmol) were combined in 10 mL ofDMF and heated at 55° C. for 18 h. After cooling, the mixture is dilutedwith 100 mL of water and extracted with 3×20 mL of ethyl acetate. Theorganics were dried, concentrated, and the residue is purified by flashchromatography using 7/3 ethyl actate/hexanes to give 3.0 g (86%) of thetitle compound as an oil. NMR

General Example E:

3-{4-[2-(1-Substitutedbenzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-isopropoxy-propionicacid methyl ester

Prepared as in General example B using2-Isopropoxy-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid methyl ester and the appropriate benzyl halide. The resultingesters were purified by flash chromatography, and could be used asstarting materials in subsequent coupling reactions, or hydrolized tofinal compounds: To hydrolize, the ester is dissolved in 2 mL of MeOHand 0.3 mL of 5N NaOH, and the mixture is heated to 50° C. for 2 h. Theorganic solvent is then removed under vacuum and the residue isdissolved in CH₂Cl₂ and 1N HCl. The aqueous layer is washed with CH₂Cl₂(2×10 mL). The organics were combined, dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude material is purified by MS/LC orflash chromatography to give the final products.

General Example F:

3-{4-[2-(1-Substituted-biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-isopropoxy-propionicacid

Prepared as in General example C by coupling3-(4-{2-[1-(4-bromo-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionicacid methyl ester and the appropriate boronic acid, followed byhydrolysis to the carboxylic acid.

The Examples provided herein are illustrative of the invention claimedherein and are not intended to limit the scope of the claimed inventionin any way.

EXEMPLIFICATION Instrumental Analysis

Infrared spectra were recorded on a Perkin Elmer 781 spectrometer. ¹HNMR spectra were recorded on a Varian 400 MHz spectrometer at ambienttemperature. Data are reported as follows: chemical shift in ppm frominternal standard tetramethylsilane on the 6 scale, multiplicity(b=broad, δ =singlet, d=doublet, t=triplet, q=quartet, qn=quintet andm=multiplet), integration, coupling constant (Hz) and assignment. ¹³CNMR were recorded on a Varian 400 MHz spectrometer at ambienttemperature. Chemical shifts are reported in ppm from tetramethylsilaneon the 6 scale, with the solvent resonance employed as the internalstandard (CDCl₃ at 77.0 ppm and DMSO-d₆ at 39.5 ppm). Combustionanalyses were performed by Eli Lilly and Company MicroanalyticalLaboratory. High-resolution mass spectra were obtained on VG ZAB 3F orVG 70 SE spectrometers. Analytical thin layer chromatography wasperformed on EM Reagent 0.25 mm silica gel 60-F plates. Visualizationwas accomplished with UV light.

PREPARATIONS Preparation 1 Preparation of toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl esterStep A (2,5-Dioxo-imidazolidin-4-yl)-acetic acid methyl ester

5-Hydantoin acetic acid (20.57 g, 0.130 mol) in MeOH (210 mL) wastreated with conc. H₂SO₄ (7 mL) and heated to reflux under N₂ for 2.5 h.The resultant clear solution was cooled and the solvent removed in vacuoto give an oil which was diluted with water (65 mL) and extracted 4times with EtOAc. The organic layer was dried (MgSO₄) and the solventremoved in vacuo to afford 19.81 g (88%) of(2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester. MS (ES⁺) Calc'dfor C₆H₉N₂O₄ (M+1) 173. Found m/z 173 (100%) ¹H NMR.

Step B [1-(4-Methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acidmethyl ester

A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester(26.6 g, 0.155 mol) in DMF (500 mL) was treated with 4-methoxybenzylchloride (26.6 g, 0.170 mol), MgSO₄ (18.6 g, 0.154 mol) and then 325mesh K₂CO₃ (42.71 g, 0.309 mol) at 0° C. The resultant mixture waswarmed to room temperature under N₂ and then heated at 45° C. for 4 h.The reaction mixture was filtered, and then aqueous 1N HCl (200 mL) wasadded to the filtrate. The filtrate was extracted with EtOAc and theorganic layer dried (MgSO₄). The solvent was removed in vacuo to give11.43 g crude product which was purified by flash chromatography using agradient of 3:1 to 1:1 hexanes:acetone to give 9.81 g (22%)[1-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methylester. MS (ES⁺) Calc'd for C₁₄H₁₇N₂O₅ (M+1) 293. Found m/z 293 (100%).¹H NMR.

Step C[1-(4-methoxy-benzyl)-3-methyl-2,5-dioxo-imidazolidin-4-yl]-acetic acidmethyl ester

A 0° C. solution of compound[1-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methylester (9.84 g, 33.7 mmol) in DMF (30 mL) was treated with sodium hydride(60% dispersion, 1.37 g, 34.3 mmol) and warmed to room temperature andstirred under N₂ for 20 minutes. The resultant mixture was cooled to 0°C. and then treated with methyl iodide (6.16 g, 43.4 mmol) and thenwarmed to room temperature and stirred for 16 h. The reaction wasquenched with aqueous 1 N HCl (60 mL) and then worked up extractivelywith EtOAc and water. The organic layer was dried (MgSO₄) and thesolvent removed in vacuo to give crude product that was purified byflash chromatography using 3:1 hexanes:actetone to afford 7.46 g (85%)[1-(4-methoxy-benzyl)-3-methyl-2,5-dioxo-imidazolidin-4-yl]-acetic acidmethyl ester. MS (ES⁺) Calc'd for C₁₅H₁₉N₂O₅ (M+1) 307. Found m/z 307(100%). ¹H NMR.

Step D4-(2-Hydroxy-ethyl)-1-(4-methoxy-benzyl)-3-methyl-imidazolidin-2-one

A solution of[1-(4-methoxy-benzyl)-3-methyl-2,5-dioxo-imidazolidin-4-yl]-acetic acidmethyl ester (7.45 g, 24.3 mmol) in methanol (100 mL) was treated withaqueous 5 N NaOH (49 mL) and heated to reflux 1 h. The reaction mixturewas cooled, the solvent removed in vacuo. The resultant residue wasacidified with aqueous 1 N HCl (300 mL) and extracted with EtOAc andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford 7.73 g (100%) acid that was utilized withoutpurification. A solution of crude acid (7.73 g, assume 24.3 mmol) in THF(100 mL) was treated dropwise with 1 M solution of borane-THF complex inTHF (146 mL, 0.145 mol) and then stirred at room temperature under N₂for 16 h. The reaction was quenched with methanol (100 mL) and stirredat room temperature for 1 h. The solvent was removed in vacuo to givecrude product that was purified by flash chromatography using 2:1hexanes:acetone to afford 4.76 g (74%)4-(2-hydroxy-ethyl)-1-(4-methoxy-benzyl)-3-methyl-imidazolidin-2-one. MS(ES⁺) Calc'd for C₁₄H₂₁N₂O₃ (M+1) 265. Found m/z 265 (100%). ¹H NMR.

Step E Toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester

A solution of4-(2-hydroxy-ethyl)-1-(4-methoxy-benzyl)-3-methyl-imidazolidin-2-one(4.75 g, 18.0 mmol), pyridine (4.98 g, 62.9 mmol) and 4-dimethyl aminopyridine (0.66 g, 5.40 mmol) in CH₂Cl₂ (200 mL) was treated withp-toluenesulfonic anhydride (9.38 g, 28.7 mmol) and the reaction stirredat room temperature for under N₂ for 1.5 h. The reaction mixture waswashed with aqueous 1 N HCl (140 mL), the organic layer was dried(MgSO₄), and the solvent removed in vacuo to afford crude product thatwas purified by flash chromatography using 3:1 hexanes:actetone toafford 6.93 g (92%) toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester.MS (ES⁺) Calc'd for C₂₁H₂₇N₂O₅S (M+1) 419. Found m/z 419 (100%). ¹H NMR.

EXEMPLIFIED COMPOUNDS Example 12-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionicacid

Step A2-(4-{2-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionicacid ethyl ester

To a mixture of toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester(0.100 g, 0.239 mmole) and2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester(0.063 g, 0.262 mmole) in anhydrous DMF (2.0 mL), is added cesiumcarbonate (0.093 g, 0.287 mmole). After heating at 65° C. for about 16hours, the reaction mixture is partitioned between ethyl acetate (5 ml)and 1.0 N HCl aq. (5 ml), the aqueous layer is extracted with more ethylacetate (2×5 ml). The combined organic layer is washed with brine (3×5ml). The organic layer is dried over Na₂SO₄, filtered, and concentratedin vacuo. Chromatography using silica gel (0-40% acetone/hexane)produces a colorless oil (0.107 g, 91%). Mass [EI+] 485 (M+H)⁺.

Step B2-Methyl-2-{2-methyl-4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionicacid ethyl ester

2-(4-{2-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionicacid ethyl ester (0.105 g, 0.217 mmole) is treated with tryethylsilane(0.064 g, 0.743 mmole) in TFA (8.0 mL) at room temperature for about 6hours. After evaporating the solvents, the residue is purified usingsilica gel (0-50% acetone/hexane). Colorless oil (0.041 g, 51%). Mass[EI+] 365 (M+H)⁺, 729 (2M+H)⁺.

Step C2-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionicacid

To a solution of2-methyl-2-{2-methyl-4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionicacid ethyl ester (0.040 g, 0.110 mmole) in DMF (2.0 mL), is added sodiumhydride (60% in mineral oil, 0.0066 g, 0.165 mmole) in one portion. Themixture is stirred for 15 minutes at room temperature, then was added4-tert-butyl-benzyl bromide (0.030 mL, 0.165 mmole). After stirring atroom temperature for 4 hours, the reaction mixture is partitionedbetween ethyl acetate (5 ml) and saturated NH₄Cl aq. (5 ml), the aqueouslayer is extracted with more ethyl acetate (2×5 ml). The combinedorganic layer is washed with brine (3×5 ml), dried over Na₂SO₄,filtered, and concentrated in vacuo. The crude product was purified bysilica gel (0-40% Acetone/Hexane). The ethyl ester obtained above istreated with a mixture of MeOH (2 mL)/5.0N NaOH (1 mL) at roomtemperature overnight, and then concentrated. The resulting residue isdiluted with water (2 mL), cooled down to 0° C., acidified to pH=2 byadding concentrated HCl dropwise. The aqueous suspension is loaded on aChem elut 1005 tube, eluted with DCM (50 mL). Evaporation of methylenechloride gives the titled compound as an colorless oil (0.022 g, 42%).Mass [EI+] 483 (M+H)⁺, [EI−] 481 (M−H)⁻.

Example 22-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-3-propyl-phenoxy)-2-methyl-propionicacid

Step A2-(4-{2-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-3-propyl-phenoxy)-2-methyl-propionicacid ethyl ester

The titled compound is prepared, according to the procedure of Example1, Step A, using toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester(0.200 g, 0.478 mmole) and 2-(4-hydroxy-3-propyl-phenoxy)-2-methyl-propionic acid ethyl ester (0.140 g, 0.526 mmole) toproduce a colorless oil (0.122 g, 50%). Mass [EI+] 513 (M+H)⁺.

Step B2-Methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-3-propyl-phenoxy}-propionicacid ethyl ester

The titled compound is prepared, according to the procedure of Example1, Step B, using2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-3-propyl-phenoxy)-2-methyl-propionicacid ethyl ester (0.120 g, 0.234 mmole) to produce a colorless oil(0.054 g, 57%). Mass [EI+] 393 (M+H)⁺, 785 (2M+H)⁺.

Step C 2-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-3-propyl-phenoxy)-2-methyl- propionic acid

The titled compound is prepared, according to the procedure of Example1, Step B, using2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-3-propyl-phenoxy}-propionicacid ethyl ester (0.054 g, 0.138 mmole) to produce a colorless oil(0.051 g, 72%). Mass [EI+] 511 (M+H)⁺, [EI−] 509 (M−H)⁻.

Example 3 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-inethyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl- propionic acid

Step A 1-(4-tert-Butyl-benzyl)-4-[3-(3-iodo-4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one

To a solution of 1-(4-tert-Butyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.630 g, 1.60 mmole) inethanol (15 mL), is added iodine (0.810 g, 3.20 mmole) followed bysilver sulfate (0.998 g, 3.20 mmole). The reaction mixture is stirred atroom temperature overnight. The precipitate is removed throughfiltration, and the solution is concentrated in vacuo. The residue ispurified by column chromatography (silica gel, gradient elution 0-20%acetone in hexane) to provide a white foamy solid (0.584 g, 70%). Mass[EI+] 521 (M+H)⁺.

Step B 1-(4-tert-Butyl-benzyl)-4-[3-(4-methoxy-3-methyl-phenyl)-propyl]-3-methyl-imidazolidin-2-one

1-(4-tert-Butyl-benzyl)-4-[3-(3-iodo-4-methoxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.300 g, 0.580 mmole), methylboronic acid (0.069 g, 1.16 mmole) and cesium carbonate (0.264 g, 1.74mmole) are mixed in dioxane (6.0 mL). After bubbling with nitrogen for15 minutes, 1,1′-bis(diphenylphosphino)ferrocence palladium (II)chloride (0.060 g, 0.015 mmole) is added. The reaction is heated at 80°C. for 4 hours. The solvent is removed on rota-vapor, and the crudeproduct is purified by column chromatography (silica gel, gradientelution 0-20% acetone in hexane) to provide a yellow oil (0.153 g, 65%).Mass [EI+] 409 (M+H)⁺, 817(M+H)⁺.

Step C 1-(4-tert-Butyl-benzyl)-4-[3-(4-hydroxy-3-methyl-phenyl)-propyl]3-3-methyl-imidazolidin-2-one

To a solution of1-(4-tert-Butyl-benzyl)-4-[3-(4-methoxy-3-methyl-phenyl)-propyl]-3-methyl-imidazolidin-2-one(0.250 g, 0.612 mmole) in DCM (2.0 mL) at −78° C., is added dropwise thesolution of BBr₃ (0.230 mL, 2.44 mmole) in methylene chloride (2.0 mL).The reaction is kept for 30 minutes at about −78° C., then warmed up to0° C. and stirred for an hour. It is then quenched by 1:1 MeOH/DCM (20mL), stirred for another hour at 0° C. The reaction mixture ispartitioned between DCM (25 mL) and water (25 mL), the organic layer isseparated, washed by brine (3×25 mL), dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude product is purified by columnchromatography (silica gel, gradient elution 0-20% acetone in hexane) toprovide a yellow oil (0.126 g, 53%). Mass [EI+] 395 (M+H)⁺, 789(M+H)⁺,[EI−] 393 (M−H)⁻.

Step D 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl- propionic acidethyl ester

1-(4-tert-Butyl-benzyl)-4-[3-(4-hydroxy-3-methyl-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.060 g, 0.152 mmol) is dissolvedin DMF (1.5 mL), to it is added ethyl 2-bromoisobutyrate (0.141 g, 0.760mmol) followed by potassium carbonate (0.105 g, 0.760 mmol). Afterheating at 50° C. overnight, the reaction mixture is diluted with ethylacetate (2 mL), washed with water (2 mL), the separated organic layer ispassed through a chem elut tube, and the tube is washed with more DCM(50 mL). Evaporation of solvent followed by chromatography on silicagel, (gradient elution 0-40% ethyl acetate in hexane) to provide an oil(0.068 g, 88%). Mass [EI+] 510 (M+H)⁺.

Step E 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl- propionic acid

2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl- propionic acidethyl ester (0.065 g, 0.128 mmole) is treated with 3:1 MeOH/5.0N NaOH (4mL) at room temperature overnight, and then concentrated. The resultingresidue is diluted with water (2 mL), cooled down to 0° C., acidified topH=2 by adding concentrated HCl dropwise. The aqueous suspension isloaded on a Chem elut tube and eluted with DCM (50 mL). Evaporation ofmethylene chloride gives the titled compound as an oil (0.060 g, 98%).Mass [EI+] 481 (M+H)⁺, [EI−] 479 (M−H)⁻.

Example 4 2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl- propionic acid

Step A 2-Methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-propionic acid ethyl ester

The titled compound is prepared, according to the procedure of Example3, Step D, using4-[3-(4-Hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one(0.445 g, 1.13 mmole) to produce an oil (0.464 g, 85%). Mass [EI+] 507(M+H)⁺.

Step B 2-(2-Iodo-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester

The titled compound is prepared, according to the procedure of Example3, Step A, using2-Methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-propionicacid ethyl ester (0.460 g, 0.960 mmole) to produce an oil (0.273 g,48%). Mass [EI+] 633 (M+H)⁺.

Step C 2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl- propionic acidethyl ester

The titled compound is prepared, according to the procedure of Example3, Step B, using2-(2-Iodo-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid ethyl ester (0.270 g, 0.430 mmole) and n-butyl boronic acid (0.218g, 0.215 mmole) to produce an oil (0.115 g, 48%). Mass [EI+] 563 (M+H)⁺.

Step D 2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl- propionic acid

The titled compound is prepared, according to the procedure of Example3, Step E, using2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid ethyl ester (0.11 g, 0.196 mmole) to produce an oil (0.029 g, 28%).Mass [EI+] 535 (M+H)⁺, [EI−] 533 (M−H)⁻. The following Examples areprepared substantially as described herein above to yield the titlecompounds:

Example 5 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-phenoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid

Yield(0.135 g, 86%). Mass [EI+] 581 (M+H)⁺, [EI−] 579 (M−H)-

Example 6 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-phenoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid

Yield(0.192 g, 52%). Mass [EI+] 581 (M+H)⁺, [EI−] 579 (M−H)-

Example 7 2-Methyl-3(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid

Yield(0.127 g, 35%). Mass [EI+] 573 (M+H)⁺, [EI−] 571 (M−H)-

Example 8 2-Methyl-3(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

Yield (0.238 g, 63%). Mass [EI+] 573 (M+H)⁺, [EI−] 571 (M−H)-

Example 92-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid

Step A 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidmethyl ester

To a solution of LDA (1.5 M in cyclohexane, 33 mL, 49.5 mmole) in THF(40 mL), at −78° C., is added dropwise a solution of2-(2-fluoro-phenoxy)-propionic acid ethyl ester (7.70 g, 36.3 mmole) inTHF (100 mL). After stirring for 30 minutes at −78° C., a solution oftoluene-4-sulfonic acid 4-iodomethyl-phenyl ester (12.8 g, 33.0 mmole)is injected to the reaction mixture. The reaction is stirred at −78° C.for one hour, then warmed up to room temperature and stirred overnight.The reaction is treated with 5.0N NaOH (50 mL) in presence of methanol(200 mL). After evaporating methanol, the aqueous solution is acidifiedwith concentrated HCl to pH=1 and is extracted with ethyl acetate (2×300mL). The combined organic layers are dried, filtered and concentrated invacuo. The residue is dissolved in MeOH (200 mL) and treated withconcentrated sulfuric acid (2 mL) at 80° C. overnight. The reactionmixture is partitioned between ethyl acetate (500 mL) and water (500mL), the organic layer is washed by brine (3×500 mL), dried, filteredand concentrated in vacuo. The compound is purified by chromatography(silica gel, gradient elution 0-20% ethyl acetate in hexane) to providean oil (6.02 g, 60%), which is then resolved by chiral HPLC to generatethe enantiomer as an oil (2.30 g). Mass [EI+] 322 (M+NH4)⁺, [EI−] 303(M−H)⁻.

Step B2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid methyl ester

The titled compound is prepared, according to the procedure of Example1, Step A, using toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester(0.888 g, 2.12 mmole) and2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acidmethylester (0.645 g, 2.12 mmole) to produce an oil (0.95 g, 81%). Mass[EI+] 551 (M+H)⁺.

Step C2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid

The titled compound is prepared, according to the procedure of Example3, Step E, using2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy}-phenyl)-2-methyl-propionic acid methyl ester (0.224 g, 0.406mmole) to produce a white foamy solid (0.199 g, 91%). Mass [EI+] 537(M+H)⁺, [EI−] 535 (M−H)⁻.

Example 103-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionic acid

The titled compound is prepared using substantially the processesdescribed herein above to produce a white foamy solid (0.0858 g, 40%).Mass [EI+] 583 (M+H)⁺, [EI−] 581 (M- H)⁻.

Example 11 3-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

The titled compound is prepared, according to the proceduressubstantially as described hereinabove to produce a white foamy solid(0.101 g, 77%). Mass [EI+] 563 (M+H)⁺, [EI−] 561 (M−H)⁻.

Example 12 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid

The titled compound is prepared, substantially as described herein aboveto yield (0.0753 g, 58%). Mass [EI+] 543 (M+H)⁺, [El-] 541 (M−H)⁻.

Example 13

Step A

A methylene chloride solution (300 ml) of 4-(4-methoxyphenyl)butanol(10.0 g, 0.055 mol) is cooled to 0° C. and stirred. Pyridiniumchlorochromate (17.8 g, 0.082 mol) is added slowly to the solution whichis stirred, placed under a drying tube and warmed to room temperatureovernight. The reaction mixture is filtered and the filtrate washed withaqueous brine then dried over sodium sulfate. Evaporation of the solventgives the crude product as an oil. Purification by flash chromatography(hexanes:ethyl acetate) gives the desired aldehyde (6.8 g). C₁₁H₁₄02(M=178.23); ¹H NMR

Step B

Potassium cyanide (10.3 g, 0.158 mol) and ammonium carbonate (38.1 g,0.396 mol) are combined in methanol (100 ml) and water (100 ml). Theproduct from Example 13, Step A (6.7 g, 0.038 mol) is added and thereaction is stirred while heating to 45° C. overnight. The reaction iscooled and the precipitate filtered and washed with water. The obtainedsolid is dissolved in THF and dried with sodium sulfate. Evaporation ofthe solvent results in a solid which is washed with ethylacetate:hexanes (50:50) then air-dried to yield the desired hydantoin(16.6 g). C₁₃H₁₆N₂O₃ (MW=248.3); ¹H NMR

Example 14

Step A

Preparation of:

To a cooled (0° C.) solution of boron tribromide (50 g, 200 mmol) inCH₂Cl₂ (50 ml) is added a solution of methyl 4-(4-methoxyphenyl)butyrate(15.5 g, 74.4 mmol) in CH₂Cl₂ (100 ml) dropwise over one hour. Afterstirring for an additional hour at 0° C., the reaction mixture istreated with 1:1 CH₃OH:CH₂Cl₂ (120 ml) with cooling and stirredovernight at ambient temperature. Concentration of the mixture gives anoil which is partitioned between ethyl acetate (150 ml) and water (150ml). The aqueous layer is extracted with ethyl acetate (2×50 ml), andthe combined organic extracts washed with water (50 ml), brine (50 ml),dried, then concentrated to give the desired phenol as an oil. C₁₁H₁₄O₃(MW=194.23); MS: m/z (M⁺+1)=195

Step B

The phenol from Step A (18.6 g, 96 mmol) is dissolved in DMF (300 ml)and treated with t-butyl 2-bromoisobutyrate (50 ml, 288 mmol), powderedK₂CO₃ (53.0 g, 384 mmol) and MgSO₄ (1.6 g, 96 mmol), and the resultingmixture heated at 75° C. overnight. After cooling to ambienttemperature, the reaction mixture is decanted into 1N aqueous HCl (300ml) and extracted with diethyl ether (3×150 ml). The remaining solidsfrom the decantation are washed several times with diethyl ether. Thediethyl ether extracts and washes are combined and washed with 1Naqueous HCl (150 ml), dried (Na₂SO₄), and concentrated to a dark oil.Purification by flash chromatography (gradient elution, hexanes to 95:5hexanes:ethyl acetate) gives the desired ether as an oil. C₁₉H₂₈O₅(MW=336.43); MS: m/z (M⁺+1)=337

Step C

The diester from Step B (10.7 g, 0.032 mol) is dissolved in dioxane (100mL) then treated with an aqueous solution (50 mL) of LiOH (1.5 g, 0.063mol). The resulting mixture is stirred at room temperature for 2 hr atwhich time TLC indicates complete reaction. The solvent is concentratedto approximately 10 mL which is then diluted with H₂O (200 mL) andwashed with ether (1×100 mL). The aqueous extract is acidified with 5 NHCl (25 mL) and extracted with ethyl acetate (2×150 mL). The combinedorganic extracts are dried over Na₂SO₄ and concentrated to give thedesired carboxylic acid (10.6 g, >99%). C₁₈H₂₆O₅ (MW=322.40); massspectroscopy: (M+NH₄+)=340.3, (M−H)=321.3

Step D

A THF solution (100 mL) of the carboxylic acid from Step C (10 g, 0.031mol) is cooled to 0° C. and treated with triethyl amine (5.6 mL, 0.040mol) followed by ethyl chloroformate (3.8 mL, 0.040 mol). A thick whiteprecipitate forms almost immediately. The reaction mixture is warmed toroom temperature, and after stirring overnight, the mixture is filtered.The filtrate is cooled to 0° C. and treated with sodium borohydride (3.5g, 0.092 mol). A solution of methanol (20 mL) in THF (40 mL) is addeddropwise over a 30-40 minute period then the resulting mixture is warmedto room temperature and stirred for 1 hour. Again the solution is cooledto 0° C. and carefully quenched by the addition of 1 N HCl (100 mL). Themixture is diluted with water (400 mL0 and extracted with CH₂Cl₂ (2×300mL). The combined organic extracts are dried over Na₂SO₄, filtered andconcentrated. The crude oil is purified by flash chromatography (5:1hexanes:ethyl acetate) to give the desired alcohol as a colorless oil(8.69 g, 88%).

Step E

The alcohol from Step D (8.7 g, 0.028 mol) is dissolved in CH₂Cl₂ andcooled to 0° C. Pyridinium chlorochromate (9.0 g, 0.042 mol) was addedto the solution in portions after which the mixture is warmed to roomtemperature. After stirring overnight the reaction mixture is filteredusing celite. The filtrate is concentrated and the resulting crude oilis purified by chromatography (10:1 hexanes:ethyl acetate) to give thedesired aldehyde as a colorless oil (4.45 g, 52%).

Step F

Potassium cyanide (1.1 g, 7.2 mmol) and ammonium carbonate (1.7 g, 18.0mmol) are combined in methanol (15 ml) and water (15 mL). The aldehydefrom Step E (1.1 g, 3.6 mmol) is added and the reaction is stirred whileheating to 50° C. After 3 hr, additional ammonium carbonate is added(1.7 g, 18.0 mmol) and the resulting mixture is stirred overnight at 50°C. The reaction is cooled to room temperature, diluted with water, thenextracted with ethyl acetate (2×). The combined organic extracts arewashed with brine, dried over Na₂SO₄, and concentrated. Purification bychromatography (gradient: 10:1 to 3:1 to 3:2 hexanes:ethyl acetate)gives the desired hydantoin (0.9 g, 66%) C₂₀H₂₈N₂O₅ (MW=376.46); massspectroscopy: (MH+-t-butyl) 321.2, (MH⁻⁾⁼375.4

Example 15

Step A

The hydantoin from Example 14 (1.0 g, 2.66 mmol) and 4-(tert-butyl)benzyl bromide (0.63 ml, 2.93 mmol) are stirred together in DMF(20 ml). Potassium carbonate (powdered,1.5 g, 10.64 mmol) and magnesiumsulfate (0.5 g, 4.00 mmol) are added and the mixture stirred at ambienttemperature overnight. The reaction mixture is carefully added to 1 Nhydrochloric acid (50 ml) and the resulting solution is extracted twicewith ethyl acetate. The organic layers are combined, washed with aqueousbrine then dried over sodium sulfate. Evaporation of the solvent andsubsequent purification by flash chromatography (hexanes:ethyl acetate)gives the desired product (1.05 g). C₃₁H₄₂N₂O₅ (MW=522.7)

Step B

The hydantoin from Example 15, Step A (0.15 g, 0.29 mmol) is stirred inethanol, sodium borohydride (0.11 g, 2.90 mmol) added slowly and themixture was stirred at ambient temperature, under a drying tube,overnight. The reaction mixture was concentrated and the residuedissolved in ethyl acetate, washed with water and aqueous brine thendried. Evaporation of the solvent and subsequent purification by flashchromatography (ethyl hexanes:ethyl acetate) gives the desired product(0.071 g). C₃₁H₄₂N₂O₄ (MW=506.7)

Step C

The product from Example 15, Step B (0.071 g, 0.14 mmol) is stirred inmethylene chloride (4 ml) with triflouroacetic acid (0.1 ml, 1.3 mmol),under a drying tube, overnight. The solvent is evaporated and subsequentpurification by flash chromatography (ethyl acetate:hexanes) gives thedesired product (0.035 g). C₂₇H₃₄N₂O₄ (MW=450.6); MS (M+, 451.3)

Example 16

C₂₅H₃₀N₂O₄ (MW=422.5); MS (M+, 423.3)

Step A

Following the procedure of Example 15, Step A, the product was obtainedusing the hydantoin from Example 14 (1.0 g, 2.66 mmol) and3,4-dimethylbenzyl chloride (Transworld, 0.42 ml, 2.93 mol). Thisreaction was heated to 50° C. to affect reaction completion, yieldingthe product (0.550 g). C₂₉H₃₈N₂O₅ (MW=494.6)

Step B

Following the procedure of Example 15, Step B, the alkylated hydantoinfrom Example 16, Step A (0.15 g, 0.3 mmol) and sodium borohydride (0.11g, 3.00 mmol) were used to yield the desired imidazolone (0.032 g).C₂₉H₃₈N₂O₄ (MW=478.6)

Step C

Following the procedure of Example 15, Step C, the imidazolone from StepB (0.032 g, 0.066 mmol) and triflouroacetic acid (0.1 ml) were used toyield the desired product (0.026 g). C₂₅H₃₀N₂O₄ (MW=422.5); MS (M+,423.3)

Example 17

The title compound is prepared using substantially the proceduresdescribed herein above. Yield: 26% for two steps. C₂₄H₂₈N₂O₅(MW=424.50); mass spectroscopy: (MH⁺)=425.3

Example 18

The title compound is prepared using substantially the proceduresdescribed herein above. C₂₆H₂₇N₃O₄ (MW=445.5); MS (M+, 446.3)

Example 19

The title compound is prepared using substantially the proceduresdescribed herein above to yield the product. C₂₄H₂₈N₂O₄ (MW=408.50);mass spectroscopy: (MH⁺)=409.2

Example 20

Step A

The hydantoin from Example 14 (0.500 g, 0.0013 mol) is dissolved in DMFand treated with 3, 5 difluoro bromobenzene (0.189 g, 0.0015 mol) andpowdered K₂CO₃ (0.718 g, 0.0052 mol). The resulting mixture is stirredat room temperature overnight. The reaction mixture is poured into 1NHCl and combined with ethyl acetate. The organic layer is extracted andwashed with brine then dried and concentrated. Purification of the crudematerial by flash chromatography (4:1 hexanes:ethyl acetate, 1:1hexanes:ethyl acetate) yields the desired hydantoin as a clear oil(0.420 g, 64%). C₂₇H₃₂F₂N₂O₅ (MW=502.23); mass spectroscopy (MH⁺)=447.1

Step B

The hydantoin from Step A (0.410 g, 0.00082 mol) is dissolved inmethylene chloride (5 ml) and treated with trifluoroacetic acid (0.315ml, 0.0041 mol) and stirred overnight. The solvent is concentrated andthe product is vacuum dried. C₂₃H₂₄F₂N₂O₅ (MW=446.17); mass spectroscopy(MH⁺)=447.2

Step C

The acid from Step B (0.428 g, 0.00096 mol) is dissolved in ethanol (20ml) and treated with sodium borohydride (0.363 g, 0.0096 mol). One hourlater, additional sodium borohydride (0.363 g) is added and the reactionis stirred overnight. Fifty milliliters of 5N HCl is added to thereaction mixture followed by water (50 ml). The aqueous solution isextracted with ethyl acetate (2×, 50 ml). The organic layer is washed,dried, and concentrated. Purification by flash chromatography (100%ethyl acetate) gives the desired acid as a burgundy solid (150 g, 36%).C₂₃H₂₄F₂N₂O₄ (MW=430.17); mass spectroscopy (MH⁺)=431.1

Example 21

Step A

A DMF solution (20 mL) of the hydantoin from Example 14 (455.2 mg, 1.21mmol) is treated sequentially with benzyl bromide (160 μL, 1.35 mmol),K₂CO₃ (0.44 g, 3.2 mmol), and MgSO₄ (0.48 g, 4.0 mmol). The resultingmixture is stirred at room temperature overnight. The reaction isquenched by the slow addition of 1 N HCl. The resulting mixture isextracted with ethyl acetate (2×75 mL). The combined organic extractsare washed with brine then dried over Na₂SO₄ and concentrated.Purification by chromatography (2:1 hexanes:ethyl acetate) gives thedesired alkylated hydantoin as a white solid (512.0 mg, 91%). C₂₇H₃₄N₂O₅(M=466.58); mass spectroscopy: (MH+-t-butyl)=411.1, (MH⁻)=465.3

Step B

A CH₂Cl₂ solution (15 mL) of the ester from Step A (495.5 mg, 1.06 mmol)is cooled to 0° C. and treated with TFA (2 mL, 26 mmol). The mixture iswarmed to room temperature and stirred overnight. The solvent isconcentrated to give the crude acid. Trace amounts of TFA are removed byconcentration from toluene (3×15 mL) after which the product is used inthe subsequent reaction without further purification.

C₂₃H₂₆N₂O₅ (MW=410.47); mass spectroscopy: (MH⁺)=411.1, (MH⁻)=409.2

Step C

The hydantoin from Step B is dissolved in ethanol (20 mL) and treatedwith NaBH₄ (400 mg, 10.5 mmol). Additional NaBH₄ is added to thereaction mixture after 3 hr (200 mg, 4.8 mmol). The resulting mixture isstirred at room temperature overnight. Additional NaBH₄ is added to thereaction mixture (370 mg, 9.7 mmol) and stirring is continued for abouttwo days. The reaction is quenched by the careful addition of 5 N HCl.The mixture is stirred for 30 minutes then diluted with H₂O andextracted with ethyl acetate. The combined organic extracts are washed,dried, and concentrated. Purification by chromatography (gradient: 100%CH₂Cl₂ to 5% methanol in CH₂Cl₂) gives the desired imidazolone as aglass-like solid (93.2 mg, 22% for two steps). C₂₃H₂₆N₂O₄ (MW=394.47);mass spectroscopy: (MH⁺)=395.1, (MH⁻)=393.2

Example 22

Step A

The corresponding hydantoin is prepared using substantially theprocedures described herein above.

Yield: 84%. C₃₁H₃₆N₂O₅ (MW=516.64); mass spectroscopy:(MH+-t-butyl)=461.2, (MH⁻)=515.4

Step B

A CH₂Cl₂ solution (15 mL) of the ester from Step A (387.8 mg, 0.751mmol) is cooled to 0° C. and treated with TFA (2 mL, 26 mmol). Themixture is warmed to room temperature and stirred overnight. The solventis concentrated to give the crude acid. Trace amounts of TFA are removedby concentration from toluene (3×15 mL) after which the product is usedin the subsequent reaction without further purification. C₂₇H₂₈N₂O₅(M=460.53) mass spectroscopy: (MH⁺)=461.2, (MH⁻)=459.3

Step C

The hydantoin from Step B is dissolved in ethanol:THF (2:1, 30 mL) andtreated with NaBH₄ (313 mg, 8.2 mmol). Additional NaBH₄ is added to thereaction mixture after 3 hr (180 mg, 4.7 mmol). The resulting mixture isstirred at room temperature overnight. The reaction is quenched by thecareful addition of 5 N HCl. The mixture is stirred for 30 minutes thendiluted with H₂O (75 mL) and extracted with ethyl acetate (2×75 mL). Thecombined organic extracts are washed, dried, and concentrated.Purification by chromatography (gradient: 100% CH₂Cl₂ to 5% methanol inCH₂Cl₂) gives the desired imidazolone as a white foam (109.0 mg, 33% fortwo steps). C₂₇H₂₈N₂O₄ (MW=444.54); mass spectroscopy: (MH⁺)=445.2,(MH⁻)=443.1

The following Examples are prepared using substantially the proceduresdescribed herein before.

Example 23

C₂₄H₂₈N₂O₄ (MW=408.50); mass spectroscopy: (MH⁺)=409.2, (MH⁻)=407.1

Example 24

C₂₆H₃₂N₂O₄ (MW=436.56); mass spectroscopy: (MH⁺) 437.2, (MH⁻)=435.1

Example 25

Step A

Following the procedure of Example 15, Step A, the product was obtainedusing the hydantoin from Example 14 (0.5 g, 1.33 mmol) and 4-ethylbenzylchloride (Aldrich, 0.2 ml, 1.46 mol). This reaction was heated to 45° C.to affect reaction completion, yielding, after purification, the product(0.41 g). C₂₉H₃₈N₂O₅ (MW=494.6); MS (M+, 495.3, M+18, 512.3)

Step B

The product from Example 25, Step A (0.4 g, 0.8 mmol) was stirred inmethylene chloride (10 ml) with trifluoroacetic acid (Aldrich, 2 ml),under a drying tube, overnight. The solvent was evaporated and theobtained residue was placed under vacuum to yield the desired carboxylicacid (0.36 g). C₂₅H₃₀N₂O₅ (MW=438.5); MS (M-, 437.1)

Step C

The product from Example 25, Step B (0.33 g, 0.75 mmol) was stirred inethanol (30 ml) and sodium borohydride (0.28 g, 7.5 mmol) added slowly.After stirring overnight, 5 N hydrochloric acid (5 ml) was added slowlyand allowed to stir for 1 hr. Water (50 ml) added and the mixture wasextracted twice with ethyl acetate. The organic layers were combined,washed with aqueous brine and dried over sodium sulfate. Evaporation ofthe solvent and subsequent purification by flash chromatography(methylene chloride:methanol) gave the desired product (0.120 g).C₂₅H₃₀N₂O₄ (MW=422.5); MS (M+, 423.3, M-, 421.1)

Example 26

Step A

A DMF solution (75 mL) of the hydantoin from Example 13(1.5 g, 6.0 mmol)is treated sequentially with benzyl bromide (1.8 mL, 15 mmol), K₂CO₃(3.7 g, 27 mmol), and MgSO₄ (4.2 g, 35 mmol). The resulting mixture isstirred at room temperature overnight. The reaction is quenched by theslow addition of 1 N HCl (100 mL). The resulting mixture is extractedwith ethyl acetate (2×100 mL). The combined organic extracts are washedwith brine then dried over Na₂SO₄ and concentrated. Purification bychromatography (5:1 hexanes:ethyl acetate) gives the desired alkylatedhydantoin as a colorless oil (1.33 g, 52%). C₂₇H₂₈N₂O₃ (MW=428.21); massspectroscopy: (MH⁺)=429.2

Step B

To a slurry of LAH (122 mg, 3.2 mmol) in THF (10 mL) at 0° C. under N₂is added the hydantoin from Step A (1.02 g, 2.38 mmol) as a solution inTHF (10 mL). After 10 minutes the reaction is quenched by the additionof 5 N HCl (4 mL) in THF (2 mL), stirred for 30 minutes, then dilutedwith H₂O (75 mL). The resulting mixture is extracted with ethyl acetate(2×75 mL). The combined organic extracts are washed with brine, driedand concentrated. Purification by chromatography (gradient: 5:1 to 1:1hexanes:ethyl acetate) gives the desired imidazolone as a colorless oil(0.873 g, 89%). C₂₇H₂₈N₂O₂ (MW=412.54); mass spectroscopy: (MH⁺)=413.1

Step C

The imidazolone from Step B (0.81 g, 2.0 mmol) is dissolved in CH₂Cl₂and cooled to 0° C. under an atmosphere of N₂. A solution of BBr₃ (600μL, 6.3 mmol) in CH₂Cl₂ (15 mL) is added dropwise, then the reactionmixture is warmed to room temperature. After 1 hr, the solution is againcooled to 0° C. and quenched by the slow addition of a methanol (10 mL)solution in CH₂Cl₂ (50 mL). The resulting mixture is extracted with H₂O(150 mL). The organic extract is washed with brine, dried over Na₂SO₄,and concentrated to give the desired phenol as a foam-like solid (0.78g, 98%). C₂₆H₂₆N₂O₂ (MW=398.51); mass spectroscopy: (MH⁺)=399.2,(MH⁻)=397.3

Step D

An ethanol solution (40 mL) of the phenol from Step C (0.78 g, 1.9 mmol)is treated sequentially with ethyl 2-bromoisobutyrate (1.5 mL, 10.2mmol), K₂CO₃ (1.4 g, 10.1 nmol), and MgSO₄ (1.2 g, 10 mmol). Theresulting mixture is heated to 50° C. for two days. The reaction isquenched by the slow addition of 1 N HCl (15 mL) then poured into 0.5 NHCl (100 mL). The resulting mixture is extracted with ethyl acetate(2×70 mL). The combined organic extracts are washed, then dried andconcentrated. Purification by chromatography (gradient: 3:1 to 1:1hexanes:ethyl acetate) gives the desired ester as a slightly yellow oil(0.79 g, 81%). C₃₂H₃₆N₂O₄ (MW=512.65); mass spectroscopy: (MH⁺)=513.3

Step E

A dioxane solution (15 mL) of the ester from Step D (0.741, 1.45 mmol)is treated with an aqueous solution (5 mL) of LiOH (120.4 mg, 5.0 mmol).After stirring overnight the solvent is concentrated and the resultingoil is diluted with H₂O (70 mL) and extracted with Et₂O (70 mL). Theaqueous extract is acidified with 1 N HCl and extracted with ethylacetate (2×70 mL). The combined organic extracts are washed, dried, andconcentrated to give the desired carboxylic acid as a slightly yellowfoam-like solid (0.601 g, 86%) C₃₀H₃₂N₂O₄ (MW=484.60); massspectroscopy: (MH⁺)=485.3, (MH⁻)=483.3

Example 273-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

Step A

2-(2-Fluoro-phenoxy)-propionic acid ethyl ester

Cesium carbonate (65.69 g, 201.61 mmol) is added to a solution of2-fluorophenol (9 mL, 100.84 mmol, d=1.256) in anhydrous DMF (300 mL) atroom temperature under an atmosphere of nitrogen. After five minutes,ethyl 2-bromopropionate (130.1 mL, 100.84 mmol, d=1.394) is addedrapidly dropwise and the resultant mixture is allowed to stir at 90° C.for 18 h. The reaction mixture is diluted with diethyl ether, thenextracted twice with 1N HCl and twice with water. The organic layer isdried, concentrated, and purified by flash chromatography (25% ether inhexanes) to provide the titled compound (20.14 g, 94%). ¹H NMR (400 MHz,CDCl₃): □ 7.07-6.96 (m 2H), 6.93-6.87 (m, 2H), 4.73, 4.71 (ABq, 1H,J=6.7 Hz).4.21-4.15 (m, 2H), 1.61 (d, 3H, J=6.7 Hz), 1.21 (t, 3H, J=6.7Hz). MS [EI+] 507 (M+H)⁺. R_(f)=0.39 in 20% acetone in hexanes.

Step B

3-(4-Benzyloxy-phenyl)-2-(2-fluoro-phenoxy)-3-hydroxy-2-methyl-propionicacid ethyl ester

A solution of LDA (49.6 mL, 99.15 mmol, 2M in cyclohexane) in anhydrousTHF (150 mL) is cooled to −78° C. in a dry ice/acetone bath and added toa solution of 2-(2-Fluoro-phenoxy)-propionic acid ethyl ester inanhydrous THF (150 mL) also cooled to −78° C. under an atmosphere ofnitrogen. After five minutes, 4-benzyloxybenzaldehyde (10.52 g, 99.15mmol) is added in one portion. After stirring for one minute, thereaction mixture is quenched with acetic acid (9.5 mL, 165.3 mmol,d=1.049) and a saturated solution of aqueous NH₄Cl (100 mL). Thebiphasic mixture is allowed to warm to room temperature and is dilutedwith diethyl ether (1 L). The organic layer is washed, dried, andconcentrated. The residue is purified by flash chromatography (20%acetone in hexanes) to provide a mixture of diastereomers of3-(4-Benzyloxy-phenyl)-2-(2-fluoro-phenoxy)-3-hydroxy-2-methyl-propionicacid ethyl ester (16.21 g, 69%). ¹H NMR (400 MHz, CDCl₃): δ 7.45-7.33(m, 7H), 7.09-6.95 (m, 6H), 5.07 (s, 2H), 4.21-4.17 (m, 2H), 3.10 (d,1H, J=5.4 Hz), 1.39 (s, 3H), 1.20 (t, 3H, J=6.1 Hz) R_(f)=0.06 in 25%acetone in hexanes.

Step C

3-(4-Benzyloxy-phenyl)-2-(2-fluoro-phenoxy)-2-methyl- propionic acidethyl ester

Boron trifluoride etherate (21.62 mL, 171.85 mmol, d=1.128) is addeddropwise rapidly to a 0° C. solution of3-(4-Benzyloxy-phenyl)-2-(2-fluoro- phenoxy)-2-methyl-propionic acidethyl ester (16.21 g, 38.19 mmol) and triethylsilane (27.45 mL, 171.85nmol, d=0.728) in anhydrous CH₂Cl₂ (150 mL). The mixture is stirred for90 minutes, gradually warming to ambient temperature. The reactionmixture is quenched with a saturated solution of aqueous sodiumcarbonate and extracted with CH₂Cl₂. The organic layer is dried overMgSO₄, concentrated in vacuo, and purified by flash chromatography (20%acetone in hexanes) to provide the titled compound (12.8 g, 82%). ¹H NMR(400 MHz, CDCl₃): δ 7.46 (d, 2H, J=6.7 Hz), 7.42 (d, 2H, J=6.7 Hz),7.39-7.33 (m, 1H), 7.26 (d, 2H, J=8.2 Hz), 7.11-7.06 (m, 1H), 7.01-6.93(m, 5H), 4.23 (q, 2H, J=7.2 Hz), 3.31, 3.21 (AB_(q), 2H, J=13.4 Hz),1.45 (s, 3H), 1.26 (t, 3H, J=7.2 Hz). R_(f)=0.25 in 20% acetone inhexanes.

Step D

2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester

3-(4-Benzyloxy-phenyl)-2-(2-fluoro- phenoxy)-2-methyl-propionic acidethyl ester (12.8 g, 31.34 mmol) is dissolved in ethanol (500 mL),treated with 10% palladium on carbon (6.0 g), and stirred under anatmosphere of hydrogen for 90 minutes. The suspension is filteredthrough celite and concentrated to provide 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (9.65g, 97%). The title compound is separated by chiral chromatography(Column OJ, 40% IPA in heptane, 1 mL/mmin, 240 nm UV. ¹H NMR (400 MHz,CDCl₃): δ 7.13 (d, 2H, J=8.0 Hz), 7.07-7.02 (m, 1H), 6.98-6.88 (m, 3H),6.74 (d, 2H, J=8.0 Hz), 6.05 (s, 1H), 4.20 (q, 2H, J=6.9 Hz), 3.24, 3.16(AB_(q), 2H, J=13.4 Hz), 1.39 (s, 3H), 1.23 (t, 3H, J=6.8 Hz).

Step E

2-(2-Fluoro-phenoxy)-3(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester

Cesium carbonate (8.23 g, 25.3 nmol) is added to a solution of2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester (2.68 g, 8.43 mmol) and toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester(3.88 g, 9.27 mmol) in DMF (30 mL). The resultant mixture is stirred at65° C. under an atmosphere of nitrogen for 18 h, then diluted with ethylacetate. The organic layer is washed with 1N HCl, water, and brine. Theorganic layer is dried, concentrated in vacuo, and purified by flashchromatography (17% acetone in hexanes) to provide the title compound(4.4 g, 93%). ¹H NMR 400 MHz, CDCl₃): δ 7.19-7.15 (m, 4H), 7.06-7.01 (m,1H), 6.97-6.87 (m, 3H), 6.83 (d, 2H, J=8.6 Hz), 6.74 (d, 2H, J=8.6 Hz),4.31, 4.27 (AB_(q) 2H, J=14.8 Hz), 4.21, 4.17 (AB_(q), 2H, J=7.2 Hz),3.96-3.92 (m, 2H), 3.76 (s, 3H), 3.60-3.53 (m, 1H), 3.33 (t, 1H, J=8.6Hz), 3.25, 3.13 (AB_(q) 2H, J=13.8 Hz), 2.994-2.83 (m, 2H), 2.82 (s,3H), 2.24-2.16 (m, 1H), 1.89-1.80 (m, 1H), 1.37 (s, 3H), 1.22 (t, 3H,J=7.2 Hz). MS [EI+] 565 (M+H)⁺. R_(f)=0.56 in 50% acetone in hexanes.

Step F

2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester

Trifluoroacetic acid (70 mL) is added dropwise to a solution oftriethylsilane (2.5 mL, 15.73 mmol, d=0.728) and2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester (4.44 g, 7.86 mmol). The reaction mixture is stirred 2h, then concentrated in vacuo. The residue is diluted with ethylacetate, then washed with a saturated solution of aqueous sodiumcarbonate, water, and brine. The organic layer is dried and concentratedto provide the title compound (3.5 g, 100%). ¹H NMR (400 MHz, CDCl₃): δ7.20 (d, 2H, J=8.7 Hz), 7.06-7.01 (m, 1H), 6.97-6.87 (m, 3H), 6.79 (d,2H, J=8.7 Hz), 5.04-4.98 (m, 1H), 4.20 (q, 2H, J=6.8 Hz), 4.02 (t, 2H,J=6.8 Hz), 3.76-3.69 (m, 1H), 3.55 (t, 1H, J=8.7 Hz), 3.26, 3.14 (ABqt2H, J=14.5 Hz), 3.21 (t, 1H, J=8.7 Hz), 2.78 (s, 3H), 2.27-2.20 (m, 1H),1.99-1.90 (m, 1H), 1.38 (s, 3H), 1.23 (t, 3H, J=6.8 Hz), 0.96 (t, 2H,J=7.7 Hz). MS [EI+] 445 (M+H)⁺. R_(f)=0.50 in 10% methanol in methylenechloride.

Step G

3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid ethyl ester

Benzyl bromide (0.02 mL, 0.172 mmol, d=1.438) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.051 g, 0.115 mmol) and sodium hydride (0.011 g,0.287 mmol, 60% suspension on mineral oil), pre- stirred for 1 h atambient temperature. The reaction mixture is stirred at ambienttemperature for 18 h, diluted with ethyl acetate, and washed with 1NHCl, water, and brine. The organic layer is dried and concentrated invacuo to provide the title compound, which is used in the next step. MS[EI+] 535 (M+H)⁺.

Step H

3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

A solution of3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy)-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxedunder nitrogen for 1 h, cooled to ambient temperature, and concentratedin vacuo. The residue is diluted with 1N HCl, extracted with CH₂Cl₂,dried, concentrated in vacuo, and purified by LCMS to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, 1H, J=8.4 Hz), 7.34-7.21(m, 6H), 7.10-7.01 (m, 4H), 6.74 (d, 2H, J=8.4 Hz), 4.46-3.36 (m, 2H),3.96 (q, 2H, J=6.0 Hz), 3.74-3.65 (m, 1H), 3.45-3.39 (m, 1H), 3.28, 3.16(AB_(q), 2H, J=14.7 Hz), 3.05 (q, 1H, J=8.6 Hz), 2.26-2.19 (m, 1H),1.93-1.86 (m, 1H), 1.41 (s, 3H). MS [EI+] 507 (M+H)⁺.

Example 283-(4-{2-[1-(4-Chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

4-Chlorobenzyl bromide (0.037 g, 0.179 mmol) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.053 g, 0.119 mmol) and sodium hydride (0.012 g,0.298 mmol, 60% suspension on mineral oil), pre- stirred for 1 h atambient temperature. The reaction mixture is stirred at ambienttemperature for 18 h, diluted with ethyl acetate, and washed. Theorganic layer is dried, concentrated, and purified by LCMS to providethe title compound. ¹H NMR (400 MHz, CDCl₃): δ 7.31-7.21 (m, 4H), 7.16(d, 2H, J=8.3 Hz), 7.11-7.00 (m, 4H), 6.74 (d, 2H, J=8.3 Hz), 4.33, 4.31(AB_(q), 2H, J=15.5 Hz), 3.96 (t, 2H, J=6.0 Hz), 3.71-3.64 (m, 1H), 3.39(t, 1H, J=8.3 Hz), 3.29, 3.17 (AB_(q), 2H, J=14.3 Hz), 3.01 (t, 1H,J=8.3 Hz), 2.84 (s, 3H), 2.25-2.20 (m, 1H), 1.93-1.84 (m, 1H), 1.41 (s,3H). MS [ES⁺] m/z exact mass calcd for C₂₉H₃₁N₂O₅ 541.1906, found541.1913.

Example 292-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

4-Trifluoromethylbenzyl bromide (0.03 mL, 0.169 mmol, d=1.546) andtetrabutyl ammonium iodide (catalytic amount) are added to a 0° C.suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.050 g, 0.112 mmol) and sodium hydride (0.011 g,0.281 mmol, 60% suspension on mineral oil), and pre-stirred for 1 h atambient temperature. The reaction mixture is stirred at ambienttemperature for 18 h, diluted with ethyl acetate, and washed with 1NHCl, water, and brine. The organic layer is dried, concentrated, andpurified by LCMS. ¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, 1H, J=7.8 Hz),7.35 (d, 1H, J=7.8 Hz), 7.25-7-21 (m, 3H), 7.16 (d, 1H, J=7.8 Hz),7.08-6.95 (m, 4H), 6.73 (d, 2H, J=7.8 Hz), 4.45, 4.37 (AB_(q), 2H,L=15.0 Hz), 3.95 (t, 2H, J=5.9 Hz), 3.68-3.60 (m, 1H), 3.38 (t, 1H,J=8.5 Hz), 3.29, 3.15 (ABqt 2H, J=13.7 Hz), 3.02-2.97 (m, 1H), 2.84 (s,3H), 2.25-2.19 (m, 1H), 1.92-1.83 (m, 1H), 1.39 (s, 3H). MS [ES⁺] m/zexact mass calcd for C₃₀H₃₁N₂O₅F₄ 575.2169, found 575.2172.

Example 302-(2-Fluoro-phenoxy)-2-methyl-3(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid Step A

2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

3-Trifluoromethylbenzyl bromide (0.03 mL, 0.175 mmol, d=1.565) andtetrabutyl ammonium iodide (catalytic amount) are added to a 0° C.suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.052 g,0.117 mmol) and sodium hydride (0.012 g, 0.292 mmol, 60% suspension onmineral oil), and pre-stirred for 1 h at ambient temperature. Thereaction mixture is stirred at ambient temperature for 18 h, dilutedwith ethyl acetate, and washed with 1N HCl, water, and brine. Theorganic layer is dried, concentrated, and carried into the next step. MS[EI+] 603 (M+H)⁺.

Step B

2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester and 5NNaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h,cooled to ambient temperature, and concentrated in vacuo. The residue isdiluted with 1N HCl, extracted with CH₂Cl₂, dried, concentrated invacuo, and purified by LCMS to provide the title compound. ¹H NMR (400MHz, CDCl₃): δ 7.53-7.42 (m, 2H), 7.29-6.93 (m, 7H), 6.85-6.73 (m, 3H),4.49-4.29 (m, 2H), 3.99-3.95 (m, 2H), 3.81-3.68 (m, 1H), 3.46-3.41 (m,1H), 3.28, 3.16 (AB_(q), 2H, J=13.7 Hz), 3.09-3.04 (m, 1H), 2.86 (d, 3H,J=5.6 Hz), 2.25-2.21 (m, 1H), 1.93-1.87 (m, 1H), 1.40 (s, 3H). MS (ES⁺]m/z exact mass calcd for C₃₀H₃₁N₂O₅F₄ 575.2169, found 575.2156.

Example 312-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid Step A

2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester

3-Methoxybenzyl bromide (0.02 mL, 0.172 mmol, d=1.436) and tetrabutylammonium iodide (catalytic amount) are added to a 0° C. suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.051 g,0.115 mmol) and sodium hydride (0.011 g, 0.287 mmol, 60% suspension onmineral oil), and pre-stirred for 1 h at ambient temperature. Thereaction mixture is stirred at ambient temperature for 18 h, dilutedwith ethyl acetate, and washed with 1N HCl, water, and brine. Theorganic layer is dried over MgSO₄, concentrated in vacuo, and carriedinto the next step. MS [EI+] 565 (M+H)⁺.

Step B

2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester

A solution of2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxedunder nitrogen for 1 h, cooled to ambient temperature, and concentrated.The residue is diluted with 1N HCl, extracted with CH₂Cl₂, dried,concentrated, and purified by LCMS to provide the title compound. ¹H NMR(400 MHz, CDCl₃): δ 7.33-7.20 (m, 6H), 7.10-7.01 (m, 3H), 6.81-6.73 (m,3H), 4.36, 4.30 (AB_(q), 2H, J=14.9 Hz), 3.95 (t, 2H, J=6.5 Hz),3.71-3.68 (m, 1H), 3.45-3.40 (m, 1H), 3.29, 3.17 (AB_(q), 2H, J=14.0Hz), 3.08-3.03 (m, 1H), 2.85 (s, 3H), 2.24-2.20 (m, 1H), 1.94-1.85 (m,1H), 1.41 (s, 3H). MS [ES⁺] m/z exact mass calcd for C₃₀H₃₄N₂O₆537.2401, found 537.2418.

Example 323-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid Step A

2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester

Cesium carbonate (6.12 g, 18.76 nmol) is added to a solution of2-(2-Fluoro-phenoxy)-3-(4-hydroxy- phenyl)-2-methyl-propionic acid ethylester 1.99 g, 6.26 mmol) and toluene-4-sulfonic acid2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester(2.88 g, 6.88 mmol) in DMF (20 mL). The resultant mixture is stirred at65° C. under an atmosphere of nitrogen for 18 h, then diluted with ethylacetate. The organic layer is washed with 1N HCl, water, and brine. Theorganic layer is dried over MgSO₄, concentrated in vacuo, and purifiedby flash column chromatography (17% acetone in hexanes) to provide thetitle compound (3.4 g, 97%). ¹H NMR (400 MHz, CDCl₃): δ 7.19 (d, 2H,J=5.4 Hz), 7.17 (d, 2H, J=5.4 Hz), 7.07-7.01 (m, 1H), 6.97-6.87 (m, 3H),6.83 (d, 2H, J=8.6 Hz), 6.74 (d, 2H, J=8.6 Hz), 4.32, 4.28 (AB_(q) 2H,J=14.6 Hz), 4.20 (q, 2H, J=7.5 Hz), 3.94 (t, 2H, J=5.9 Hz), 3.77 (s,3H), 3.60-3.53 (m, 1H), 3.33 (t, 1H, J=8.6 Hz), 3.26, 3.14 (AB_(q), 2H,J=14.0 Hz), 2.92 (t, 1 h, J=8.6 Hz), 2.82 (s, 3H), 2.24-2.17 (m, 1H),1.89-1.82 (m, 1H), 1.38 (s, 3H), 1.23 (t, 3H, J=7.5 Hz). MS [EI+] 565(M+H)⁺. R_(f)=0.48 in 50% acetone in hexanes.

Step B

2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester

Trifluoroacetic acid (55 mL) is added dropwise to a solution oftriethylsilane (1.95 mL, 12.18 mmol, d=0.728) and2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester (3.44 g, 6.09 mmol). The reaction mixture is stirredunder nitrogen at ambient temperature for 2 h, then concentrated. Theresidue is diluted with ethyl acetate, then washed. The organic layer isdried and concentrated in vacuo to provide the title compound (2.7 g,78%). ¹H NMR (400 MHz, CDCl₃): δ 7.20 (d, 2H, J=8.7 Hz), 7.06-7.01 (m,1H), 6.97-6.87 (m, 3H), 6.79 (d, 2H, J=8.7 Hz), 5.04-4.98 (m, 1H), 4.20(q, 2H, J=6.8 Hz), 4.02 (t, 2H, J=6.8 Hz), 3.76-3.69 (m, 1H), 3.55 (t,1H, J=8.7 Hz), 3.26, 3.14 (AB_(q), 2H, J=14.5 Hz), 3.21 (t, 1H, J=8.7Hz), 2.78 (s, 3H), 2.27-2.20 (m, 1H), 1.99-1.90 (m, 1H), 1.38 (s, 3H),1.23 (t, 3H, J=6.8 Hz), 0.96 (t, 2H, J=7.7 Hz). MS [EI+] 445 (M+H)⁺.R_(f)=0.38 in 10% methanol in methylene chloride.

Step C

3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid ethyl ester

Benzyl bromide (0.02 mL, 0.179 mmol, d=1.438) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.053 g, 0.119 mmol) and sodium hydride (0.012 g,0.298 mmol, 60% suspension on mineral oil), pre- stirred for 1 h atambient temperature. The reaction mixture is stirred at ambienttemperature for 18 h, diluted with ethyl acetate, and washed with 1NHCl, water, and brine. The organic layer is dried over MgSO₄ andconcentrated in vacuo to provide the title compound, which is carriedinto the next step. MS [EI+] 535 (M+H)⁺.

Step H3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

A solution of3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxedunder nitrogen for 1 h, cooled to ambient temperature, and concentratedin vacuo. The residue is diluted with 1N HCl, extracted with CH₂Cl₂,dried, concentrated, and purified by LCMS to provide the title compound.¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, 1H, J=8.4 Hz), 7.34-7.21 (m, 6H),7.10-7.01 (m, 4H), 6.74 (d, 2H, J=8.4 Hz), 4.46-3.36 (m, 2H), 3.96 (q,2H, J=6.0 Hz), 3.74-3.65 (m, 1H), 3.45-3.39 (m, 1H), 3.28, 3.16 (AB_(q)2H, J=14.7 Hz), 3.05 (q, 1H, J=8.6 Hz), 2.26-2.19 (m, 1H), 1.93-1.86 (m,1H), 1.41 (s, 3H). MS [ES⁺] m/z exact mass calcd for C₂₉H₃₂N₂O₅F507.2295, found 507.2308.

Example 333-(4-{2-[1-(4-Chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

4“Chlorobenzyl bromide (0.035 g, 0.172 mmol) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.051 g, 0.115 mmol) and sodium hydride (0.011 g,0.287 mmol, 60% suspension on mineral oil), pre- stirred for 1 h atambient temperature. The reaction mixture is stirred at ambienttemperature for 18 h, diluted with ethyl acetate, and washed. Theorganic layer is dried, concentrated, and purified by LCMS to providethe title compound. ¹H NMR (400 MHz, CDCl₃): δ 7.31-7.22 (m, 5H),7.15-7.01 (m, 5H), 6.74 (d, 2H, J=7.8 Hz), 4.34 (d, 2H, J=14.3 Hz), 3.96(s, 2H), 3.73-3.71 (m, 1H), 3.46-3.40 (m, 1H), 3.28, 3.16 (AB_(q), 2H,J=14.3 Hz), 3.08-3.06 (m, 1H), 2.85 (s, 3H), 2.23-2.20 (m, 1H),1.91-1.89 (m, 1H), 1.41 (s, 3H). MS [ES⁺] m/z exact mass calcd forC₂₉H₃₁N₂O₅FCl541.1906, found 541.1909.

Example 342-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

Step A

2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

4-Trifluoromethylbenzyl bromide (0.03 mL, 0.169 mmol, d=1.546) andtetrabutyl ammonium iodide (catalytic amount) are added to a 0° C.suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.050 g,0.113 mmol) and sodium hydride (0.011 g, 0.281 mmol, 60% suspension onmineral oil), and pre-stirred for 1 h at ambient temperature. Thereaction mixture is stirred at ambient temperature for 18 h, dilutedwith ethyl acetate, and washed with 1N HCl, water, and brine. Theorganic layer is dried, concentrated, and carried into the next step. MS[EI+] 603 (M+H)⁺.

Step B

2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester and 5NNaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h,cooled to ambient temperature, and concentrated in vacuo. The residue isdiluted with 1N HCl, extracted with CH₂Cl₂, dried, concentrated, andpurified by LCMS to provide the title compound. ¹H NMR (400 MHz, CDCl₃):δ 7.56-7.51 (m 1H), 7.48-7.33 (m, 2H), 7.26-7.21 (m, 3H), 7.11-6.98 (m,4H), 6.74 (d, 2H, J=8.4 Hz), 4.49-4.34 (m, 2H), 3.98 (t, 2H, J=5.3 Hz),3.74-3.67 (m, 1H), 3.42 (t, 1H, J=8.4 Hz), 3.35, 3.23 (AB_(q), 2H,J=14.5 Hz), 3.08-3.03 (m, 1H), 2.86 (s, 3H), 2.27-2.20 (m, 1H),1.95-1.88 (m, 1H), 1.42 (s, 3H). MS [ES⁺] m/z exact mass calc'd forC₃₀H₃₁N₂O₅F₄ 575.2169, found 575.2175.

Example 352-(2-Fluoro-phenoxy)-2-methyl-3-(4-[{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid Step A

2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

3-Trifluoromethylbenzyl bromide (0.03 mL, 0.165 mmol, d=1.565) andtetrabutyl ammonium iodide (catalytic amount) are added to a 0° C.suspension of 2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.049 g,0.110 mmol) and sodium hydride (0.011 g, 0.276 mmol, 60% suspension onmineral oil), pre-stirred for 1 h at ambient temperature. The reactionmixture is stirred at ambient temperature for 18 h, diluted with ethylacetate, and washed. The organic layer is dried, concentrated, andcarried into the next step. MS [EI+] 603 (M+H)⁺.

Step B

2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

A solution of 2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)propionic acid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h, cooled to ambient temperature, andconcentrated in vacuo. The residue is diluted with 1N HCl, extractedwith CH₂Cl₂, dried, concentrated, and purified by LCMS to provide thetitle compound. ³H NMR (400 MHz, CDCl₃): δ 7.51-7.41 (m, 2H), 7.28-7.19(m, 3H), 7.09-6.99 (m, 4H), 6.81-6.73 (m, 3H), 4.48-4.28 (m, 2H),3.98-3.94 (m, 2H), 3.73-3.65 (m, 1H), 3.42 (t, 1H, J=8.7 Hz), 3.29, 3.15(AB_(q), 2H, J=13.6 Hz), 3.06-3.01 (m, 1H), 2.85 (d, 3H, J=5.6 Hz),2.25-2.21 (m, 1H), 1.93-1.87 (m, 1H), 1.40 (s, 3H). MS [ES⁺] m/z exactmass calcd for C₃₀H₃₁N₂O₅F₄ 575.2169, found 575.2172.

Example 362-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester Step A

2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester

3-Methoxybenzyl bromide (0.03 mL, 0.179 mmol, d=1.436) and tetrabutylammonium iodide (catalytic amount) are added to a 0° C. suspension of2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.053 g,0.119 mmol) and sodium hydride (0.012 g, 0.298 mmol, 60% suspension onmineral oil), and pre-stirred for 1 h at ambient temperature. Thereaction mixture is stirred at ambient temperature for 18 h, dilutedwith ethyl acetate, and washed. The organic layer is dried,concentrated, and carried into the next step. MS [EI+] 565 (M+H)⁺.

Step B

2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester

A solution of2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester and 5N NaOH (0.2 mL) in ethanol (2 mL) is refluxedunder nitrogen for 1 h, cooled to ambient temperature, and concentratedin vacuo. The residue is diluted with 1N HCl, extracted with CH₂Cl₂,dried through a Varian ChemElut cartridge, concentrated in vacuo, andpurified by LCMS to provide the title compound. ¹H NMR (400 MHz, CDCl₃):δ 7.26-7.19 (m, 3H), 7.08-6.99 (m, 4H), 6.83-6.78 (m, 3H), 6.74 (d, 2H,J=8.4 Hz), 4.36, 4.30 (AB_(q) 2H, J=14.9 Hz), 3.95 (t, 2H, J=6.5 Hz),3.77 (s, 3H), 3.65-3.58 (m, 1H), 3.37 (t, 1H, J=8.8 Hz), 3.28, 3.16(AB_(q), 2H, J=14.4 Hz), 2.97 (t, 1H, J=8.8 Hz), 2.83 (s, 3H), 2.25-2.17(m, 1H), 1.92-1.83 (m, 1H), 1.40 (s, 3H). MS [ES⁺] m/z exact mass calcdfor C₃₀H₃₄N₂O₆F 537.2401, found 537.2413.

Example 373-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid Step A

3-(4-Benzyloxy-phenyl)-2-methyl-acrylic acid ethyl ester

Triethyl-2-phosphonopropionate (22.2 mL, 103.65 mmol, d=1.111) is addedto a 0° C. slurry of sodium hydride (4.15 g, 103.65 μmmol, 60%dispersion on mineral oil) in anhydrousTHF (150 mL), then allowed towarm to ambient temperature over thirty minutes. The slurry is re-cooledto 0° C. and 4-benzyloxybenzaldehyde (20 g, 94.23 mmol) is added in oneportion as a solid. The reaction mixture is stirred 18 h at ambienttemperature, then diluted with diethyl ether. The organic layer iswashed with a saturated solution of aqueous ammonium chloride, water,and brine, then dried over MgSO₄ and concentrated in vacuo. The residueis purified by flash chromatography to provide the title compound (24.3g, 87%). ¹H NMR (400 MHz, CDCl₃): δ 7.67 (s, 1H), 7.46-7.35 (m, 6H),7.01 (d, 2H, J=8.1 Hz), 5.10 (s, 2H), 4.28 (q, 2H, J=7.2 Hz), 2.15 (s,3H), 1.36 (t, 3H, J=7.2 Hz). R_(f)=0.31 in 20% acetone in hexanes.

Step B

3-(4-Benzyloxy-phenyl)-2,3-dihydroxy-2-methyl-propionic acid ethyl ester

3-(4-Benzyloxy-phenyl)-2-methyl-acrylic acid ethyl ester (13.84 g, 46.70mmol) is added to a solution of acetone (235 mL), 4-methylmorpholineN-oxide (6.02 g, 51.37 mmol), tert-butyl alcohol (24 mL), and 4% osmiumtetroxide in water (14.7 mL), then stirred 20 h. The reaction isquenched with sodium hydrosulphite (4.7 g, 26.81 mmol), diluted withethyl acetate, washed with water. The organic layer is dried,concentrated, and purified by flash chromatography to provide the titlecompound (12.9 g, 83%). ¹H NMR (400 MHz, CDCl₃): δ 7.44-7.32 (m, 7H),6.82 (d, 2H, J=9.3 Hz), 5.06 (s, 2H), 4.78 (d, 1H, J=6.0 Hz), 4.32-4.27(m, 2H), 3.52 (s, 1H), 2.66 (d, 1H, J=7.3 Hz), 1.33 (t, 3H, J=7.3 Hz),1.17 (s, 3H). R_(f)=0.48 in 50% acetone in hexanes.

Step C

3-(4-Benzyloxy-phenyl)-2-hydroxy-2-methyl-propionic acid ethyl ester

Boron trifluoride etherate was added to a 0° C. solution of3-(4-Benzyloxy-phenyl)-2,3-dihydroxy-2-methyl- propionic acid ethylester (12.9 g, 38.96 mmol) and triethylsilane (28 mL, 175.3 mmol,d=0.728) in anhydrous CH₂Cl₂, then the reaction is allowed to graduallywarm to ambient temperature over 3 h. The reaction is quenched with asaturated aqueous solution of sodium bicarbonate and extracted withadditional CH₂Cl₂. The organic layer is dried, concentrated, andseparated by chiral chromatography to provide the title compound (11.7g, 96%). ¹H NMR (400 MHz, CDCl₃): δ 7.44-7.33 (m, 5H), 7.12 (d, 2H,J=6.85 Hz), 6.90 (d, 2H, J=6.85 Hz), 5.04 (s, 2H), 4.22-4.14 (m, 2H),3.03 (d, 1H, J=13.69 Hz), 2.87 (d, 1H, J=13.69 Hz), 1.48 (s, 3H), 1.27(t, 3H, J=7.34 Hz). R_(f)=0.60 in 50% acetone in hexanes.

Step D

2-Hydroxy-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester

3-(4-Benzyloxy-phenyl)-2-hydroxy-2-methyl-propionic acid ethyl ester(5.9 g, 18.77 mmol) is dissolved in ethanol (375 mL), treated with 10%palladium on carbon (2.95 g), and stirred under an atmosphere ofhydrogen for 2 h. The suspension is filtered and concentrated to providethe title compound. ¹H NMR (400 MHz, CDCl₃): δ 7.00 (d, 2H, J=8.3 Hz),6.69 (d, 2H, J=8.3 Hz), 4.18-4.13 (m, 2H), 2.99, 2.83 (AB_(q), 2H,J=13.7 Hz), 1.47 (s, 3H), 1.24 (t, 3H, J=7.34 Hz). R_(f)=0.58 in 50%acetone in hexanes.

Step E

2-Hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester

Cesium carbonate (21.9 g, 67.3 mmol) is added to a solution of2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (5.03 g, 22.4 mmol) and toluene-4-sulfonicacid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo- imidazolidin-4-yl]-ethylester (10.33 g, 24.7 mmol) in DMF (100 mL). The resultant mixture isstirred at 55° C. under an atmosphere of nitrogen for 18 h, then dilutedwith ethyl acetate. The organic layer is washed. The organic layer isdried, concentrated, and purified by flash chromatography to provide thetitle compound (735 g, 70%). ¹H NMR (400 MHz, CDCl₃): δ 7.16 (d, 2H,J=8.7 Hz), 7.07 (d, 2H, J=7.9 Hz), 6.82 (d, 2H, J=7.9 Hz), 6.70 (d, 2H,J=8.7 Hz), 4.31, 4.27 (AB_(q), 2H, J=15.1 Hz), 4.19-4.11 (m, 2H), 3.91(t, 2H, J=7.2 Hz), 3.77 (s, 3H), 3.59-3.52 (m, 1H), 3.32 (t, 1H, J=8.7Hz), 3.01-2.83 (m, 6H), 2.81 (s, 3H), 2.23-2.15 (m, 1H), 1.88-1.80 (m,1H), 1.45 (s, 3H), 1.26 (t, 6H, J=6.65 Hz), 0.87 (t, 3H, J=6.5 Hz).R_(f)=0.4¹ in 50% acetone in hexanes.

Step F

2-Butoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester

A slurry of 2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester (7.35 g, 15.62 mmol) and sodium hydride (2.5 g, 62.5mmol, 60% dispersion on mineral oil) in DMF (50 mL) i stirred for 45minutes, then cooled to 0° C. Iodobutane (36 mL, 312 mmol, d=1.617) and18-crown-6 16.5 g, 62.5 mmol) are added, then the reaction mixture isstirred 18 h at ambient temperature and diluted with ethyl acetate. Theorganic layer is washed, then dried concentrated in vacuo, and dilutedwith ethanol (400 mL) and 5N NaOH (40 mL). The reaction mixture isrefluxed for 1 h, cooled to ambient temperature, and concentrated invacuo. The residue is washed, dried, concentrated, and re-dissolved inethanol (300 mL). Concentrated H₂SO₄ (30 mL) is added to the reactionsolution, then the mixture is refluxed 1 h, cooled to ambienttemperature, concentrated, and diluted with ethyl acetate. The organiclayer is washed, dried, and concentrated to provide the title compound(5.3 g, 65%). ¹H NMR (400 MHz, CDCl₃): δ 7.17 (d, 2H, J=8.8 Hz), 7.09(d, 2H, J=8.8 Hz), 6.84 (d, 2H, J=8.8 Hz), 6.70 (d, 2H, J=8.8 Hz), 4.32,4.28 (AB_(q), 2H, J=14.7 Hz), 4.17-4.11 (m, 2H), 3.93 (t, 2H, J=5.9 Hz),3.78 (s, 3H), 3.61-3.53 (m, 3H), 3.40-3.31 (m, 3H), 2.97-2.89 (m, 3H),2.97-2.89 (m, 3H), 2.81 (s, 3H), 2.25-2.15 (m, 1H), 1.89-1.81 (m, 1H),1.59-1.49 (m, 2H), 1.42-1.33 (m, 2H), 1.29 (s, 3H), 1.24 (t, 3H, J=7.2Hz), 0.91 (t, 3H, J=7.2 Hz). R_(f)=0.43 in 50% acetone in hexanes.

Step G

2-Butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester

Trifluoroacetic acid (110 mL) is added dropwise to a solution of2-Butoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester(5.31 g, 10.1 mmol) and triethylsilane (3.22 mL, 20.2 mmol, d=0.728).The reaction mixture is stirred at ambient temperature for 4 h,concentrated in vacuo, and diluted with ethyl acetate. The solution iswashed, then dried, concentrated, and purified by flash chromatographyto provide the title compound (4.1 g, 100%). ¹H NMR (400 MHz, CDCl₃): δ7.09 (d, 2H, J=8.4 Hz), 6.74 (d, 2H, J=8.4 Hz), 5.36 (s, 1H), 4.17-4.07(m, 2H), 4.02-3.96 (m, 2H), 3.76-3.68 (m, 2H), 3.55 (t, 1H, J=8.8 hz),3.40-3.31 (m, 2H), 3.20 (t, 1H, J=8.0 Hz), 2.95, 2.91 (AB_(q), 2H,J=13.6 Hz), 2.76 (s, 3H), 2.24-2.18 (m, 1H), 1.97-1.88 (m, 1H),1.58-1.51 (m, 2H), 1.41-1.31 (m, 2H), 1.27 (s, 3H), 1.22 (t, 3H, J=7.2Hz), 0.89 (t, 3H, J=7.2 Hz). R_(f)=0.44 in 10% CH₃OH in CH₂Cl₂.

Step H

3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid ethyl ester

Benzyl bromide (0.0.21 mL, 0.174 mmol, d=1.438) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.047 g,0.116 mmol) and sodium hydride (0.012 g, 0.29 mmol, 60% suspension onmineral oil), pre-stirred for 1 h at ambient temperature. The reactionmixture is stirred at ambient temperature for 48 h, diluted with ethylacetate, and washed with 1N HCl and water. The organic layer is dried,concentrated, and used in the next step. MS [EI+] 497 (M+H)⁺.

Step I

3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid

A solution of3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxedunder nitrogen for 1 h, cooled to ambient temperature, and concentrated.The residue is diluted with 1N HCl, extracted with CH₂Cl₂, dried,concentrated, and purified by LCMS to provide the title compound. ¹H NMR(400 MHz, CDCl₃): δ 7.33-7.22 (m, 5H), 7.07 (d, 2H, J=8.6 Hz), 6.71 (d,2H, J=8.6 Hz), 4.39, 4.35 (AB_(q), 2H, J=15.3 Hz), 3.94 (t, 2H, J=5.7Hz), 3.69-3.62 (m, 1H), 3.58-3.52 (m, 1H), 3.50-3.44 (m, 1H), 3.40 (t,1H, J=9.1 Hz), 3.04-3.01 (m, 1H), 3.02, 2.94 (ABqt 2H, J=13.9 Hz), 2.85(s, 3H), 2.25-2.18 (m, 1H), 1.92-1.85 (m, 1H), 1.62-1.54 (m, 1H), 1.46(s, 3H), 1.42-1.32 (m, 2H), 0.92 (t, 3H, J=7.2 Hz). MS [EI+] 469 (M+H)⁺,[EI−] 467 (M−H)⁺.

Example 38 2-Butoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid Step A2-Butoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester

3-Methoxybenzyl bromide (0.024 mL, 0.170 mmol, d=1.436) and tetrabutylammonium iodide (catalytic amount) are added to a 0° C. suspension of2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.046 g, 0.114 mmol) and sodium hydride (0.011 g, 0.28mmol, 60% suspension on mineral oil), pre- stirred for 1 h at ambienttemperature. The reaction mixture is stirred at ambient temperature 48h, diluted with ethyl acetate, and washed with 1N HCl and water. Theorganic layer is dried, concentrated, and used in the next step. MS[EI+] 527 (M+H)⁺.

Step B 2-Butoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid

A solution of2-Butoxy-3-(4-{2-(1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) isrefluxed under nitrogen for 1 h, cooled to ambient temperature, andconcentrated in vacuo. The residue is diluted with 1N HCl, extracted,dried, concentrated, and purified by LCMS to provide the title compound.¹H NMR (400 MHz, CDCl₃): δ 7.22 (t, 1H, J=8.0 Hz), 7.07 (d, 2H, J=8.5Hz), 6.83-6.79 (m, 3H), 6.72 (d, 2H, J=8.5 Hz), 4.38, 4.30 (AB_(q), 2H,J=15.1 Hz), 3.95 (t, 2H, J=6.0 Hz), 3.78 (s, 3H), 3.69-3.62 (m, 1H),3.60-3.54 (m, 1H), 3.50-3.45 (m, 1H), 3.50-3.45 (m, 1H), 3.40 (t, 1H,J=9.0 Hz), 3.03-3.00 (m, 1H), 3.01, 2.95 (AB_(q), 2H, J=14.6 Hz), 2.85(s, 3H), 2.26-2.19 (m, 1H), 1.92-1.85 (m, 1H), 1.62-1.55 (m, 2H), 1.48(s, 3H), 1.42 (m, 2H), 0.93 (t, 3H, J=7.0 Hz). MS [EI+] 499 (M+H)⁺,[EI−] 497 (M−H)⁺.

Example 39 2-Butoxy-3-(4-{2-[1-(4-chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid

4-Phenylbenzyl chloride (0.031 g, 0.152 mmol) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.041 g,00.101 mmol) and sodium hydride (0.010 g, 0.25 mmol, 60% suspension onmineral oil), pre-stirred for 1 h at ambient temperature. The reactionmixture is stirred at ambient temperature 48 h, diluted with ethylacetate, and washed with 1N HCl and water. The organic layer is dried,concentrated, and purified by LCMS to provide the title compound. ¹H NMR(400 MHz, CDCl₃): δ 7.58-7.53 (m, 5H), 7.43 (t, 2H, J=7.9 Hz), 7.35 (d,1H, J=7.5 Hz), 7.33 (d, 2H, J=7.9 Hz), 7.05 (d, 2H, J=8.8 Hz), 6.72 (d,2H, J=8.8 Hz), 4.44, 4.38 (AB_(q), 2H, J=14.7 Hz), 3.96 (t, 3H, J=6.3Hz), 3.71-3.64 (m, 1H), 3.58-3.53 (m, 1H), 3.49-3.42 (m, 2H), 3.06, 3.04(AB_(q,) 2H, J=13.7 Hz), 2.99, 2.93 (AB_(q), 2H, J=13.7 Hz), 2.86 (s,3H), 2.27-2.21 (m, 1H), 1.93-1.87 (m, 1H), 1.60-1.53 (m, 2H), 1.47 (s,3H), 1.40-1.31 (m, 2H), 0.92 (t, 3H, J=7.4 Hz). MS [EI+] 545 (M+H)⁺,[EI-] 543 (M- H)⁺.

Example 402-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid Step A

2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

3-Trifluoromethylbenzyl bromide (0.037 g, 0.157 mmol) and tetrabutylammonium iodide (catalytic amount) are added to a 0° C. suspension of2-Butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.043 g, 0.105 mmol) andsodium hydride (0.010 g, 0.26 mmol, 60% suspension on mineral oil),pre-stirred for 1 h at ambient temperature. The reaction mixture isstirred at ambient temperature for 48 h, diluted with ethyl acetate, andwashed with 1N HCl and water. The organic layer is dried over MgSO₄,concentrated in vacuo, and used in the next step. MS [El+] 565 (M+H)⁺.

Step B2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxedunder nitrogen for 1 h, cooled to ambient temperature, and concentrated.The residue is diluted with 1N HCl, extracted with CH₂Cl₂, dried,concentrated, and purified by LCMS to provide the title compound. ¹H NMR(400 MHz, CDCl₃): δ 7.51-7.38 (m, 4H), 7.04 (d, 2H, J=8.8 Hz), 6.69 (d,2H, J=8.8 Hz), 4.46, 4.34 (AB_(q), 2H, J=14.9 Hz), 3.94 (t, 2H, J=5.7Hz), 3.68-3.60 (m, 1H), 3.57-3.52 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (t,1H, J=8.8 Hz), 2.98, 2.92 (ABqt 2H, J=14.4 Hz), 2.83 (s, 3H), 2.25-2.18(m, 1H), 1.91-1.83 (m, 1H), 1.59-1.52 (m, 2H), 1.45 (s, 3H), 1.39-1.30(m, 2H), 0.91 (t, 3H, J=7.2 Hz). MS [EI+] 537 (M+H)⁺, [EI−] 535 (M−H)⁺.

Example 41 2-Butoxy-3-(4-{2-[1-(4-chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid

4-Chlorobenzyl chloride (0.04 g, 0.174 mmol) and tetrabutyl ammoniumiodide (catalytic amount) are added to a 0° C. suspension of2-butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester (0.047 g,0.116 mmol) and sodium hydride (0.012 g, 0.29 mmol, 60% suspension onmineral oil), pre-stirred for 1 h at ambient temperature. The reactionmixture is stirred at ambient temperature 48 h, diluted with ethylacetate, and washed with 1N HCl and water. The organic layer is dried,concentrated, and purified by LCMS to provide the title compound. ¹H NMR(400 MHz, CDCl₃): δ 7.27 (d, 2H, J=8.7 Hz), 7.17 (d, 2H, J=8.7 Hz), 7.07(d, 2H, J=8.7 Hz), 7.71 (d, 2H, J=8.7 Hz), 4.34, 4.32 (AB_(q), 2H,J=15.0 Hz), 3.95 (t, 3H, J=5.9 Hz), 3.69-3.62 (m, 1H), 3.61-3.55 (m,1H), 3.51-3.45 (m, 1H), 3.38 (t, 1H, J=8.7 Hz), 3.04-2.93 (m, 3H), 2.84(s, 3H), 2.26-2.18 (m, 1H), 1.92-1.84 (m, 1H), 1.62-1.54 (m, 2H), 1.49(s, 3H), 1.42-1.33 (m, 3H), 0.93 (t, 3H, J=7.3 Hz). MS [EI+] 503 (M+H)⁺,[EI−] 501 (M−H)⁺.

Example 42 2-Butoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid:

A solution of 2-Butoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester and 5NNaOH (0.2 mL) in ethanol (2 mL) is refluxed under nitrogen for 1 h,cooled to ambient temperature, and concentrated. The residue is dilutedwith 1N HCl, extracted with CH₂Cl₂, dried, concentrated, and purified byLCMS to provide the title compound (0.024 g, 84%). ¹H NMR (400 MHz,CDCl₃): δ 7.16 (d, 2H, J=140.1 Hz), 7.08 (d, 2H, J=8.4 Hz), 6.83 (d, 2H,J=10.1 Hz), 6.70 (d, 2H, J=8.4 Hz), 4.32, 4.28 (AB_(q), 2H, J=14.7 Hz),3.92 (t, 2H, J=6.1 Hz), 3.78 (s, 3H), 3.61-3.44 (m, 3H), 3.31 (t, 1H,J=8.5 Hz), 3.00, 2.92 (AB_(q), 2H, J=14.0 Hz), 2.93 (t, 1H, J=8.5 Hz),2.82 (s, 3H), 2.23-2.16 (m, 1H), 1.89-1.81 (m, 1H), 1.61-1.54 (m 2H),1.43 (s, 3H), 1.41-1.32 (m, 2H), 0.91 (t, 3H, J=7.3 Hz). MS [EI+] 499(M+H)⁺, [EI−] 497 (M−H)⁺.

Example 43 2-Ethoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid Step A2-Ethoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester

A slurry of 22-Hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester (3.75 g, 7.97 mmol) and sodium hydride (1.28 g, 31.88mmol, 60% dispersion on mineral oil) in DMF (30 mL) is stirred for 45minutes, then cooled to 0° C. Iodoethane (12.75 mL, 159.38 mmol, d=1.95)and 18-crown-6 (8.43 g, 31.88 mmol) are added, then the reaction mixtureis stirred 18 h at ambient temperature, then diluted with ethyl acetate.The organic layer is washed, dried, concentrated, and purified by flashchromatography (20% acetone in hexanes) to provide the title compound(3.23 g, 80%). ¹H NMR (400 MHz, CDCl₃): δ 7.17(d, 2H, J=8.6 Hz), 7.08(d, 2H, J=8.6 Hz), 6.83 (d, 2H, J=9.1 Hz), 6.70 (d, 2H, J=9.1 Hz), 4.31,4.27 (AB_(q), 2H, J=14.5 Hz), 4.17-4.11 (m, 2H), 3.93 (t, 2H, J=6.4 Hz),3.77 (s, 3H), 3.60-3.53 (m, 1H), 3.48-3.39 (m, 2H), 3.32 (t, 1H, J=8.6Hz), 2.98-2.89 (m, 3H), 2.81(s, 3H), 2.24-2.16 (m, 1H), 1.88-1.80 (m,1H), 1.29 (s, 3H), 1.25-1.15 (m, 6H). R_(f)=0.54 in 50% acetone inhexanes.

Step B 2-Ethoxy-3-(4-{2-[i-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid

A solution of2-ethoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester (0.038 g, 0.076 mmol) and 5N NaOH (0.2 mL) isrefluxed for 1 h, cooled to ambient temperature, and concentrated. Theresidue is diluted with CH₂Cl₂, washed, dried, and concentrated in vacuoto provide the title compound (0.027 g, 77%). ¹H NMR (400 MHz, CDCl₃): δ7.16 (d, 2H, J=8.7 Hz), 7.07 (d, 2H, J=8.1 Hz), 6.83 (d, 2H, J=8.7 Hz),6.70 (d, 2H, J=8.1 Hz), 4.31, 4.27 (Abq, 2H, J=14.9 Hz), 3.92 (t, 2H,J=6.2 Hz), 3.78 (s, 3H), 3.59-3.52 (m, 3H), 3.33 (t, 1H, J=8.2 Hz),3.03-2.91 (m, 3H), 2.81 (s, 3H), 2.21-2.17 (m, 1H), 1.90-1.81 (m, 1H),1.43 (s, 3H), 1.20 (t, 3H, J=7.0 Hz). MS [ES⁺] m/z exact mass calcd forC₂₆H₃₅N₂O₆ 471.2495, found 471.2507.

Example 442-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

Step A2-Hydroxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

Cesium carbonate (8.72 g, 26.76 mmol) is added to a solution of2-hydroxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid ethyl ester (2.0 g, 8.92 mmol) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (4.34 g, 9.51 mmol) in DMF (50 mL). The resultant mixture isstirred at 55° C. under an atmosphere of nitrogen for 18 h, then dilutedwith ethyl acetate. The organic layer is washed, dried, concentrated,and purified by flash chromatography (25% acetone in hexanes) to providethe title compound. ¹H NMR (400 MHz, CDCl₃): δ 7.95 (s, 1H), 7.50 (d,2H, J=8.2 Hz), 7.32 (d, 2H, J=8.2 Hz), 7.03 (d, 2H, J=8.2 Hz), 6.65 (d,2H, J=8.2 Hz), 4.40, 4.32 (AB_(q), 2H, J=14.7 Hz), 4.14-4.07 (m, 2H),3.91 (t, 2H, J=5.7 Hz), 3.61-3.55 (m, 1H), 3.33 (t, 1H, J=8.2 Hz),2.96-2.79 (m, 6H), 2.22-2.15 (m, 1H), 1.87-1.80 (m, 1H), 1.40 (s, 3H),1.21 (t, 3H, J=7.4 Hz). R_(f)=0.38 in 50% acetone in hexanes.

Step B

2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

A slurry of 2-hydroxy-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethylester (0.509 g, 1.00 mmol) and sodium hydride (0.16 g, 4.00 mmol, 60%dispersion on mineral oil) in DMF (3 mL) is stirred for 45 minutes, thencooled to 0° C. Iodoethane (1.60 mL, 20.02 mmol, d=1.95) and 18-crown-6(1.06 g, 4.00 mmol) are added, then the reaction mixture is stirred 18 hat ambient temperature, then diluted with ethyl acetate. The organiclayer is washed, dried, concentrated, and purified by flashchromatography (20% acetone in hexanes) to provide the title compound(3.23 g, 80%). MS [EI+] 537 (M+H)⁺. R_(f)=0.44 in 50% acetone inhexanes.

Step C2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid ethyl ester (0.19 g, 0.347 mmol) and 5N NaOH (0.5 mL) in ethanol (5mL) is refluxed for 1 h, cooled to ambient temperature, andconcentrated. The residue is diluted with CH₂Cl₂, washed, dried, andconcentrated in vacuo to provide the title compound. ¹H NMR (400 MHz,CDCl₃): δ 7.63 (d, 2H, J=8.4 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.08 (d, 2H,J=8.7 Hz), 6.76 (d, 2H, J=8.7 Hz), 4.37, 4.35 (AB_(q), 2H, J=16.4 Hz),3.99-3.89 (m, 2H), 3.63-3.53 (m, 1H), 3.43-3.23 (m, 2H), 2.98 (t, 1H,J=8.8 Hz), 2.86, 2.84 (AB_(q), 2H, J=15.4 Hz), 2.71 (s, 3H), 2.51-2.49(m, 3H), 2.23-2.13 (m, 1H), 1.86-1.74 (m, 1H), 1.15 (s, 3H), 1.08 (t,3H, J=6.9 Hz). MS [ES⁺] m/z exact mass calcd for C₂₆H₃₂N₂O₅F₃ 509.2263,found 509.2288.

Example 45 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-propoxy- propionic acid

The title compound is prepared using procedures substantially asdescribed herein and purified by LCMS to provide the title compound(0.017 g, 34% after two steps). ¹H NMR (400 MHz, CDCl₃): δ 7.48 (d, 2H,J=8.0 Hz), 7.29 (d, 2H, J=7.2 Hz), 7.01 (d, 2H, J=7.2 Hz), 6.63 (d, 2H,J=8.0 Hz), 4.45, 4.39 (AB_(q), 2H, J=15.4 Hz), 3.96 (t, 2H, J=6.0 Hz),3.69-3.62 (m, 1H), 3.57-3.52 (m, 1H), 3.46-3.37 (m, 3H), 3.04-2.93 (m,4H), 2.85 (s, 3H), 2.28-2.20 (m, 1H), 1.93-1.84 (m, 1H), 1.67-1.58 (m,2H), 1.49 (s, 3H), 0.93 (t, 3H, J=7.4 Hz). MS [EI+] 523 (M+H)⁺, [EI−]521 (M−H)⁺.

Example 462-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The title compound is prepared substantially using the proceduresdescribed herein and purified by LCMS to provide the title compound(0.022 g, 52% after two steps). ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, 2H,J=8.3 Hz), 7.36 (d, 2H, J=8.3 Hz), 7.07 (d, 2H, J=9.0 Hz), 6.71 (d, 2H,J=9.0 Hz), 4.46, 4.38 (AB_(q), 2H, J=15.2 Hz), 3.96 (t, 2H, J=5.5 Hz),3.67-3.61 (m, 1H), 3.60-3.54 (m, 1H), 3.50-3.45 (m, 1H), 3.39 (t, 1H,J=9.0 Hz), 3.03-2.92 (m, 3H), 2.85 (s, 3H), 2.27-2.20 (m, 1H), 1.93-1.84(m, 1H), 1.62-1.54 (m, 2H), 1.48 (s, 3H), 1.41-1.32 (m, 2H), 0.92 (t,3H, J=6.9 Hz). MS [EI+] 537 (M+H)⁺, [EI-] 535 (M−H)⁺.

Example 472-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

Trifluoroacetic acid (70 mL) is added dropwise to a solution of2-Ethoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (3.19 g, 6.40 mmol) and triethylsilane (2.04 mL, 12.8mmol, d=0.728). The reaction mixture is stirred at ambient temperaturefor 4 hours, concentrated, and diluted with ethyl acetate. The solutionis washed, then dried, and concentrated in vacuo to provide the titlecompound (2.2 g, 92%). ¹H NMR (400 MHz, CDCl₃): δ 7.11 (d, 2H, J=9.3Hz), 6.76 (d, 2H, J=9.3 Hz), 4.19-4.10 (m, 2H), 4.04-3.98 (m, 2H),3.77-3.69 (m, 1H), 3.56 (t, 1H, J=8.8 Hz), 3.51-3.38 (m, 2H), 3.22 (t,1H, J=8.8 Hz), 2.96, 2.94 (AB_(q), 2H, J=14.0 Hz), 2.78 (s, 3H),2.27-2.20 (m, 1H), 1.99-1.92 (m, 1H). MS [EI+] 379 (M+H)⁺.

Step A2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

4-(Trifluoromoxy)benzyl bromide (0.03 mL, 0.19 mmol) and tetrabutylammonium iodide (catalytic amount)are added to a 0° C. suspension of2-Ethoxy-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester (0.048 g, 0.127 mmol) and sodium hydride (0.013 g, 0.32mmol, 60% suspension on mineral oil), pre-stirred for 1 h at ambienttemperature. The reaction mixture is stirred at ambient temperature for90 minutes, diluted with ethyl acetate, and washed. The organic layer isdried, concentrated, and used in the next step. MS [EI+] 553 (M+H)⁺.

Step B2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid ethyl ester and 5N NaOH (0.3 mL) in ethanol (3 mL) is refluxed for1 h, cooled to ambient temperature, and concentrated. The residue isdiluted with CH₂Cl₂, , dried, and concentrated in vacuo to provide thetitle compound (0.022 g, 32% after two steps). ¹H NMR (400 MHz, CDCl₃):δ 7.24-7.19 (m, 1H), 7.09 (d, 2H, J=8.3 Hz), 6.83-6.78 (m, 3H), 6.69 (d,2H, J=8.3 Hz), 4.38, 4.28 (AB_(q), 2H, J=14.8 Hz), 3.94-3.91 (m, 3H),3.77 (s, 3H), 3.60-3.53 (m, 3H), 3.36 (t, 1H, J=9.0 Hz), 3.04-2.92 (m,1H), 1.89-1.83 (m, 1H), 1.40 (s, 3H), 1.23 (t, 3H, J=6.9 Hz). MS [EI+]525 (M+H)⁺, [EI-] 523 (M−H)⁺. R_(f)=0.27 in 10% CH₃OH in CH₂Cl₂.

Example 48 2-Ethoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid

The title compound is prepared using substantially the proceduresdescribed herein, and purified by LCMS to provide the title compound(0.022g, 32% after two steps). ¹H NMR (400 MHz, CDCl₃): δ 7.22 (t, 1H,J=7.7 Hz), 7.06 (d, 2H, J=8.3 Hz), 6.83-6.79 (m, 3H), 6.72 (d, 2H, J=7.1Hz), 4.37, 4.29 (AB_(q), 2H, J=14.8 Hz), 3.95 (t, 2H, J=6.3 Hz),3.68-3.52 (m, 6H), 3.39 (t, 3H, J=8.5 Hz), 3.04-2.93 (m, 3H), 2.84 (s,3H), 2.26-2.20 (m, 1H), 1.92-1.85 (m, 1H), 1.49 (s, 3H), 1.24 (t, 3H,J=7.1 Hz). MS [EI+] 471 (M+H)⁺, [EI−] 469 (M−H)⁺.R_(f)=0.27 in 10% CH₃OHin CH₂Cl₂.

Example 492-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The title compound is prepared using substantially the proceduresdescribed purified by LCMS to provide the title compound (0.022g, 32%after two steps). ¹H NMR (400 MHz, CDCl₃): δ 7.33 (t, 1H, J=8.2 Hz),7.17 (d, 1H, J=7.5 Hz), 7.13-7.06 (m, 4H), 6.72 (d, 2H, J=8.9 Hz), 4.42,4.34 (AB_(q), 2H, J=15.3 Hz), 3.96 (t, 2H, J=5.6 Hz), 3.71-3.52 (m, 3H),3.41 (t, 1H, J=8.3 Hz), 3.05-2.93 (m, 3H), 2.85 (s, 3H), 2.27-2.20 (m,1H), 1.94-1.85 (m, 1H), 1.47 (s, 3H), 1.23 (t, 3H, J=7.3 Hz). MS [EI+]525 (M+H)⁺, [EI−] 523 (M- H)⁺.

Example 50 2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)- propionic acid

The title compound is prepared using substantially the proceduresdescribed herein and purified by LCMS to provide the title compound. ¹HNMR (400 MHz, CDCl₃): δ 7.54-7.42 (m, 4H), 7.07 (d, 2H, J=8.3 Hz), 6.70(d, 2H, J=9.3 Hz), 4.47, 4.37 (AB_(q), 2H, J=15.3 Hz), 3.96 (t, 2H,J=6.4 Hz), 3.73-3.65 (m, 1H), 3.64-3.51 (m, 2H), 3.42 (t, 1H, J=8.3 Hz),3.05 (t, 1H, J=7.2 Hz), 3.01, 2.95 (AB_(q), 2H, J=14.3 Hz), 2.86 (s,3H), 2.27-2.20 (m, 1H), 1.94-1.87 (m, 1H), 1.46 (s, 3H), 1.23 (t, 3H,J=7.2 Hz). MS [EI+] 509 (M+H)⁺, [EI−] 507 (M−H)⁺.

Example 513-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-ethoxy-2-methyl-propionicacid

and purified by chromatotron (CH₃OH/CH₂Cl₂ gradient) to provide thetitle compound (0.033g, 55%). ¹H NMR (400 MHz, CDCl₃): δ 7.58-7.52 (m,4H), 7.43 (t, 2H, J=7.8 Hz), 7.35-7.31 (m, 3H), 7.05 (d, 2H, J=7.8 Hz),6.72 (d, 2H, J=8.5 Hz), 4.45, 4.37 (ABqt 2H, J=14.8 Hz), 3.95 (t, 2H,J=5.6 Hz), 3.64-3.52 (m, 3H), 3.40 (t, 1H, J=8.3 Hz), 3.02-2.91 (m, 3H),2.85 (s, 3H), 2.25-2.20 (m, 1H), 1.91-1.85 (m, 1H), 1.46 (s, 3H), 1.23(t, 3H, J=7.2 Hz). MS [ES⁺] m/z exact mass calcd for C₃₁H₃₇N₂O₅517.2702, found 517.2711. R_(f)=0.31 in 10% CH₃OH in CH₂Cl₂.

Example 52 3-(4-{2-[1-(3,4-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

and purified by flash chromatography to provide the title compound(0.42g, 63%). ¹H NMR (400 MHz, CDCl₃): δ 7.26-723 (m, 3H), 7.19 (d, 2H,J=8.3 HzO, 7.11-7.04 (m, 3H), 6.91 (d, 2H, J=8.3 Hz), 6.92-6.90 (m, 1H),6.75 (d, 2H, J=8.3 Hz), 4.21, 4.15 (AB_(q), 2H, J=14.8 Hz), 3.87 (t, 2H,J=6.6 Hz), 3.59-3.53 (m, 1H), 3.30n (t, 1H, J=8.2 Hz), 3.23, 3.03(AB_(q), 2H, J=13.1 Hz), 2.91 (t, 1H, J=8.2 hz), 2.74 (s, 3H), 2.16-2.10(m, 1H), 1.81-1.76 (m, 1H), 1.42 (s, 3H). MS [EI+] 525 (M+H)⁺, [EI−] 523(M−H)⁺.

Example 532-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

and concentrated in vacuo to provide the title compound (0.029g, 83%).¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, 2H, J=8.6 Hz), 7.36 (d, 2H, J=8.6Hz), 7.07 (d, 2H, J=8.6 Hz), 6.70 (d, 2H, J=8.6 Hz), 4.45, 4.37 (AB_(q),2H, J=15.6 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.66-3.51 (m, 3H), 3.37 (t, 1H,J=8.6 Hz), 3.03-2.92 (m, 3H), 2.84 (s, 3H), 2.26-2.19 (m, 1H), 2.26-2.19(m, 1H), 1.42 (s, 3H), 1.22 (t, 3H, J=7.0 Hz). MS [EI+] 509 (M+H)⁺,[EI−] 507 (M−H)⁺.

Example 542-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The title compound is prepared using substantially the proceduresdescribed herein and concentrated in vacuo to provide the title compound(0.036 g, 88%). ¹H NMR (400 MHz, CDCl₃): δ 7.55 (d, 2H, J=8.6 Hz), 7.36(d, 2H, J=8.6 Hz), 7.07 (d, 2H, J=8.6 Hz), 6.70 (d, 2H, J=8.6 Hz), 4.45,4.37 (AB_(q), 2H, J=15.6 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.66-3.51 (m, 3H),3.37 (t, 1H, J=8.6 Hz), 3.03-2.92 (s, 3H), 2.26-2.19 (m, 1H), 1.91-1.84(m, 1H), 1.42 (s, 3H), 1.22 (t, 3H, J=7.0 Hz). MS [EI+] 509 (M+H)⁺,[EI−] 507 (M- H)⁺.

Example 55 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acidStep A 3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester

Cesium carbonate (2.18 g, 6.702 mmol) is added to a solution of3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.55g, 5.155 mmol) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (3.19 g, 5.67 mmol) in DMF (30 mL). The resultant mixture isstirred at 55° C. under an atmosphere of nitrogen for 18 h, then dilutedwith ethyl acetate. The organic layer is washed, then dried,concentrated, and purified by flash chromatography (17% acetone inhexanes) to provide the title compound (3.46 g, 97%). ¹H NMR (400 MHz,CDCl₃): δ 7.57 (d, 2H, J=7.01 Hz), 7.37 (d, 2H, J=7.1 Hz), 7.23-7.19 (m,4H), 7.13 (d, 2H, J=8.7 Hz), 6.97 (t, 1H, J=7.1 Hz), 6.87-6.80 (m, 4H),6.67 (d, 2H, J=8.7 Hz), 4.79, 4.07 (AB_(q), 2H, J=15.0 Hz), 4.47, 4.43(AB_(q), 2H, J=15.0 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.92-3.87 (m, 2H), 3.80(s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 2H, J=8.7 Hz), 3.24, 3.10 (AB_(q),2H, J=14.2 Hz), 3.00 (t, 1H, J=7.9 Hz), 2.21-2.14 (m, 1H), 1.87-1.78 (m,1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)⁺.R_(f)=0.49 in 50% acetone in hexanes.

Step B 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester

Trifluoroacetic acid (60 mL) is added dropwise to a solution of3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (3.46 g, 5.01 mmol) and triethylsilane (1.6 mL, 10.0mmol, d=0.728). The reaction mixture is stirred at ambient temperaturefor 2 h, concentrated, and diluted with ethyl acetate. The solution iswashed, then dried, and concentrated in vacuo to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, 2H, J=8.2 Hz), 7.38 (d,2H, J=8.2 Hz), 7.23-7.14 (m, 4H), 6.97 (t, 1H, J=7.4 Hz), 6.82 (d, 2H,J=7.4 Hz), 6.78 (d, 2H, J=7.4 Hz), 4.44, 4.38 (AB_(q), 2H, J=15.6 Hz),4.20 (q, 2H, J=7.4 Hz), 4.07-3.99 (m, 2H), 3.96-3.89 (m, 1H), 3.47 (t,1H, J=8.2 Hz), 3.27, 3.09 (AB_(q), 2H, J=14.1 Hz), 3.04, 3.02 (ABq, 1H,J=6.7 Hz), 2.08-1.99 (m, 1H), 1.98-1.92 (m, 1H), 1.38 (s, 3H), 1.21 (t,3H, J=6.7 Hz) MS [EI+] 571 (M+H)⁺, [EI−] 569 (M−H)⁺. R_(f)=0.07 in 33%acetone in hexanes.

Step C 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acidethyl ester

A slurry of2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester (0.544 g, 0.953 mmol) and sodium hydride (0.042 g, 1.05mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1 h,then cooled to 0° C. Iodomethane (0.60 mL, 9.53 mmol, d=2.28) is added,then the reaction mixture is stirred 18 h at ambient temperature anddiluted with ethyl acetate. The organic layer is washed, dried,concentrated, and purified by flash chromatography to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, 2H, J=8.0 Hz), 7.37 (d,2H, J=8.0 Hz), 7.26-7.19 (m, 2H), 7.15 (d, 2H, J=8.9 Hz), 6.97 (t, 1H,J=8.0 Hz), 6.82 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.9 Hz), 4.46, 4.38(AB_(q), 2H, J=15.1 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.97 (t, 2H, J=7.1 Hz),3.67-3.59 (m, 1H), 3.78 (t, 1H, J=8.9 Hz), 3.26, 3.10 (AB_(q), 2H,J=14.2 Hz), 2.99 (t, 1H, J=8.9 Hz), 2.85 (s, 3H), 2.28-2.21 (m, 1H),1.93-1.84 (m, 1H), 1.39 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+]. 585(M+H)⁺. R_(f)=0.35 in 50% acetone in hexanes.

Step D 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

A solution of2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester and 5N NaOH (0.7 mL) in ethanol (6 mL) is refluxed for1 h, cooled to ambient temperature, and concentrated. The residue isdiluted with CH₂Cl₂, washed, dried, and concentrated to provide thetitle compound (0.186 g, 100%). ¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, 2H,J=8.3 Hz), 7.35 (d, 2H, J=8.3 Hz), 7.24-7.17 (m, 4H), 7.00 (t, 1H, J=7.4Hz), 6.89 (d, 2H, J=7.4 Hz), 6.73 (d, 2H, J=8.3 Hz), 4.45, 4.37 (ABq,2H, J=15.7 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.68-3.62 (m, 1H), 3.38 (t, 1H,J=8.3 Hz), 3.32, 3.10 (AB_(q), 2H, J=12.9 Hz), 3.00 (t, 1H, J=8.3 Hz),2.84 (s, 3H), 2.27-2.19 (m, 1H), 1.92-1.85 (m, 1H), 1.39 (s, 3H). MS[EI+] 557 (M+H)⁺, [EI−] 555 (M−H)⁺.

Example 56 3-(4-{2-[3-Ethyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acidStep A 3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester

Cesium carbonate (2.49 g, 7.647 mmol) is added to a solution of3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.77g, 5.88 mmol) and toluene-4-sulfonic acid 2-[3-(4-methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (3.64 g, 6.47 mmol) in DMF (40 mL). The resultant mixture isstirred at 55° C. under an atmosphere of nitrogen for 18 h, then dilutedwith ethyl acetate. The organic layer is washed, then dried,concentrated, and purified by flash chromatography (acetone/hexanesgradient) to provide the title compound (3.80 g, 94%). ¹H NMR (400 MHz,CDCl₃): δ 7.57 (d, 2H, J=8.4 Hz), 7.37 (d, 2H, J=7.8 Hz), 7.23-7.19 (m,4H), 7.13 (d, 2H, J=8.4 Hz), 6.97 (t, 1H, J=7.8 Hz), 6.86 (d, 2H, J=8.4Hz), 6.81 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=7.8 Hz), 4.66, 4.20 (AB_(q),2H, J=14.9 Hz), 4.47, 4.43 (AB_(q), 2H, J=15.5 Hz), 4.20 (q, 2H, J=7.1Hz), 3.89-3.85 (m, 2H), 3.80 (s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 1H,J=9.1 Hz), 3.26, 3.08 (AB_(q), 2H, J=13.6 Hz), 3.00 (t, 1H, J=9.1 Hz),2.20-2.14 (m, 1H), 1.87-1.78 (m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1Hz). MS [EI+] 691 (M+H)⁺. R_(f)=0.46 in 50% acetone in hexanes.

Step B

2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)- imidazolidin-4-yl-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester

Trifluoroacetic acid (66 mL) is added dropwise to a solution of3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (3.80 g, 5.50 mmol) and triethylsilane (1.76 mL, 11.0mmol, d=0.728). The reaction mixture is stirred at ambient temperaturefor 4 hours, concentrated in vacuo, and diluted with ethyl acetate. Thesolution is washed, then dried, and concentrated to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, 2H, J=7.7 Hz), 7.38 (d,2H, J=7.7 Hz), 7.22 (t, 2H, J=9.1 Hz), 7.15 (d, 2H, J=9.1 Hz), 6.97 (t,1H, J=7.7 Hz), 6.82 (d, 2H, J=7.7 Hz), 6.78 (d, 2H, J=9.1 Hz), 4.41 (q,2H, J=14.8 Hz), 4.22, 4.18 (ABq, 2H, J=7.0 Hz), 4.04-4.01 (m, 2H),3.97-3.90 (m, 1H), 3.43 (t, 1H, J=8.4 Hz), 3.26, 3.10 (AB_(q), 2H,J=14.1 Hz), 3.04, 3.02 (ABq, 1H, J=7.0 Hz), 2.08-1.99 (m, 1H), 1.98-1.90(m, 1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.0 Hz). MS [EI+] 571 (M+H)⁺,[EI−] 569 (M−H)⁺. R_(f)=0.17 in 33% acetone in hexanes.

Step C

3-(4-{2-[3-Ethyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester

A slurry of2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester (0.500 g, 0.875 mmol) and sodium hydride (0.039 g, 0.96mmol, 60% dispersion on mineral oil) in DMF (10 mL) is stirred for 1hour, then cooled to 0° C. Iodoethane (0.70 mL, 8.75 mmol, d=1.975) isadded, then the reaction mixture is stirred 18 hours at ambienttemperature and diluted with ethyl acetate. The organic layer is washed,dried, and concentrated to provide the title compound. ¹H NMR (400 MHz,CDCl₃): δ 7.55 (d, 2 h, J=8.8 Hz), 7.37 (d, 2H, J=8.0 Hz), 7.21 (t, 2H,J=8.8 Hz), 7.15 (d, 2H, J=8.0 Hz), 6.96 (t, 1H, J=7.2 Hz), 6.82 (d, 2H,J=7.2 Hz), 6.74 (d, 2H, J=8.8 Hz), 4.43, 4.39 (AB_(q), 2H, J=15.2 Hz),4.22, 4.17 (AB_(q), 2H, J=7.2 Hz), 3.96 (t, 1H, J=6.4 Hz), 3.85-3.78 (m,1H), 3.61-3.55 (m, 1H), 3.35 (t, 1H, J=8.8 Hz), 3.26, 3.12 (AB_(q), 2H,J=13.6 Hz), 3.16-3.07 (m, 2H), 2.99 (t, 1H, J=8.0 Hz), 2.26-2.19 (m,1H), 1.90-1.83 (m, 1H), 1.39(s, 3H), 1.21 (t, 3H, J=7.2 Hz), 1.14 (t,3H, J=7.2 Hz). MS [EI+] 599 (M+H)⁺.

Step D 3-(4-{2-[3-Ethyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

A solution of3-(4-{2-[3-Ethyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (0.31 g, 0.518 mmol) and 5N NaOH (1 mL) in ethanol (9mL) is refluxed for 1 hour, cooled to ambient temperature, andconcentrated. The residue is diluted with CH₂Cl₂, washed, dried, andconcentrated in vacuo to provide the title compound (0.256 g, 87%). ¹HNMR (400 MHz, CDCl₃): δ 7.54 (d, 2H, J=7.6 Hz), 7.35 (d, 2H, J=8.4 Hz),7.21-7.17 (m, 4H), 6.97 (t, 1H, J=7.6 Hz), 6.88 (d, 2H, J=7.6 Hz), 6.72(d, 2H, J=8.4 Hz), 4.42, 4.38 (AB_(q), 2H, J=15.1 Hz), 3.94 (t, 2H,J=5.9 Hz), 3.87-3.81 (m, 1H), 3.62-3.53 (m, 1H), 3.36 (t, 1H, J=8.4 Hz),3.31, 3.08 (AB_(q), 2H, J=8.4 Hz), 3.15-3.08 (m, 1H), 3.00 (t, 1H, J=8.4Hz), 2.23-2.19 (m, 1H), 1.89-1.82 (m, 1H), 1.37 (s, 3H), 1.13 (t, 3H,J=6.7 Hz). MS [EI+] 571 (M+H)⁺, [EI−] 569 (M−H)⁺.

Example 573-(4-{2-[3-(2-Methoxy-ethyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid

The title compound is prepared using substantially the proceduresdescribed herein, and concentrated in vacuo to provide the titlecompound (0.139 g, 88%). ¹H NMR (400 MHz, CDCl₃): δ 7.54 (d, 2 h, J=7.5Hz), 7.35 (d, 2H, J=8.3 Hz), 7.22-7.17 (m, 4H), 6.97 (t, 1H, J=7.5 Hz),6.88 (d, 2H, J=8.3 Hz), 6.72 (d, 2H, J=8.3 Hz), 4.42, 4.40 (ABq, 2H,J=15.8 Hz), 3.95-3.90 (m, 3H), 3.69-3.63 (m, 1H), 3.55-3.63 (m, 2H),3.33 (s, 3H), 3.41-3.23 (m, 3H), 3.11-3.01 (m, 2H), 2.73-2.34 (m, 1H),1.91-1.87 (m, 1H), 1.38(s, 3H). MS [EI+] 601 (M+H)⁺, [EI−] 599 (M−H)⁺.

Example 582-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The title compound is prepared using substantially the proceduresdescribed herein and purified by flash chromatography (25% acetone inhexanes) to provide the title compound (0.62 g, 83%). ¹H NMR (400 MHz,CDCl₃): δ 7.51-7.38 (m, 4H), 7.04 (d, 2H, J=8.8 Hz), 6.69 (d, 2H, J=8.8Hz), 4.46, 4.34 (AB_(q), 2H, J=14.9 Hz), 3.94 (t, 2H, J=5.7 Hz),3.68-3.60 (m, 1H), 3.57-3.52 (m, 1H), 3.48-3.43 (m, 1H), 3.38 (t, 1H,J=8.8 Hz), 2.98, 2.92 (AB_(q), 2H, J=14.4 Hz), 2.83 (s, 3H), 2.25-2.18(m, 1H), 1.91-1.83 (m, 1H), 1.59-1.52 (m, 2H), 1.45 (s, 3H), 1.39-1.30(m, 2H), 0.91 (t, 3H, J=7.2 Hz). MS [EI+] 537 (M+H)⁺, [EI−] 535 (M−H)⁺.

Example 593-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid

The title compound is prepared using substantially the proceduresdescribed herein and purified by LCMS to provide the title compound (5.5mg, 14% over two steps). ¹H NMR (400 MHz, CDCl₃): δ 7.56-7.51 (m, 4H),7.41 (t, 2H, J=7.8 Hz), 7.33-7.28 (m, 3H), 7.03 (d, 2H, J=8.4 Hz), 6.70(d, 2H, J=8.4 Hz), 4.43, 4.35 (AB_(q), 2H, J=15.6 Hz), 3.94 (t, 2H,J=6.0 Hz), 3.66-3.59 (m, 1H), 3.47-3.38 (m, 1H), 3.01 (t, 1H, J=7.8 Hz),2.97, 2.91 (AB_(q), 2H, J=13.8 Hz), 2.83 (s, 3H), 2.25-2.18 (m, 1H),1.91-1.83 (m, 1H), 1.58-1.51 (m, 2H), 1.45 (s, 3H), 1.38-1.29 (m, 2H),0.89 (t, 3H, J=7.8 Hz). MS [EI+] 545 (M+H)⁺, [EI−] 543 (M−H)⁺.

Example 603-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid

The title compound is prepared using substantially the proceduresdescribed herein, and purified by LCMS to provide the title compound(5.5 mg, 14% over two steps). ¹H NMR (400 MHz, CDCl₃): δ 7.31-7.21 (m,5H), 7.04 (d, 2H, J=8.6 Hz), 6.69 (d, 2H, J=8.6 Hz), 3.38, 3.32 (AB_(q),2H, J=15.7 Hz), 3.92 (t, 2H, J=6.3 Hz), 3.62-3.53 (m, 2H), 3.48-3.43 (m,1H), 3.35 (t, 1H, J=8.6 Hz), 2.99-2.93 (AB_(q), 2H, J=14.1 Hz), 2.99,2.93 (AB_(q) 2H, J=14.1 Hz), 2.95 (t, 2H, J=7.9 Hz), 2.88 (s, 3H),2.23-2.17 (m, 1H), 1.88-1.82 (m, 1H), 1.60-1.52 (m, 2H), 1.47 (s, 3H),1.38-1.32 (m, 2H), 1.23 (t, 1H, J=7.1 Hz), 0.91 (t, 3H, J=7.1 Hz). MS[EI+] 469 (M+H)⁺, [EI−] 467 (M−H)⁺.

Example 612-Methoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The title compound is prepared using substantially the proceduresdescribed herein, and purified by flash chromatography to provide thetitle compound (48 mg, 39% over two steps). ¹H NMR (400 MHz, CDCl₃): δ7.53 (d, 2H, J=8.2 Hz), 7.34 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.2 Hz),6.64 (d, 2H, J=8.2 Hz), 4.40, 4.36 (AB_(q), 2H, J=15.5 Hz), 3.90-3.87(m, 2H), 3.62-3.56 (m, 1H), 3.35 (t, 1H, J=8.2 Hz), 3.26 (s, 3H),3.04-2.87 (m, 4H), 2.82 (s, 3H), 2.20-2.16 (m, 1H), 1.87-1.80 (m, 1H),1.31 (s, 3H). MS [EI+] 495 (M+H)⁺, [EI−] 493 (M−H)⁺.

Example 622-Methoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The title compound is prepared using substantially the proceduresdescribed herein, and purified by flash chromatography to provide thetitle compound (88 mg, 63% over two steps). ¹H NMR (400 MHz, CDCl₃): δ7.53 (d, 2H, J=8.2 Hz), 7.34 (d, 2H, J=8.2 Hz), 7.07 (d, 2H, J=8.2 Hz),6.64 (d, 2H, J=8.2 Hz), 4.40, 4.36 (AB_(q), 2H, J=15.5 Hz), 3.90-3.87(m, 2H), 3.62-3.56 (m, 1H), 3.35 (t, 1H, J=8.2 Hz), 3.26 (s, 3H),3.04-2.87 (m, 4H), 2.82 (s, 3H), 2.20-2.16 (m, 1H), 1.87-1.80 (m, 1H),1.31 (s, 3H). MS [EI+] 495 (M+H)⁺, [EI−] 493 (M−H)⁺.

Example 63 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

Step A 3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester

Cesium carbonate (2.18 g, 6.702 mmol) is added to a solution of3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (1.55g, 5.155 mmol) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (3.19 g, 5.67 mmol) in DMF (30 mL). The resultant mixture isstirred at 55° C. under an atmosphere of nitrogen for 18 h, then dilutedwith ethyl acetate. The organic layer is washed, then dried,concentrated, and purified by flash chromatography (17% acetone inhexanes) to provide the title compound (3.46 g, 97%). ¹H NMR (400 MHz,CDCl₃): δ 7.57 (d, 2H, J=7.01 Hz), 7.37 (d, 2H, J=7.1 Hz), 7.23-7.19 (m,4H), 7.13 (d, 2H, J=8.7 Hz), 6.97 (t, 1H, J=7.1 Hz), 6.87-6.80 (m, 4H),6.67 (d, 2H, J=8.7 Hz), 4.79, 4.07 (AB_(q), 2H, J=15.0 Hz), 4.47, 4.43(AB_(q), 2H, J=15.0 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.92-3.87 (m, 2H), 3.80(s, 3H), 3.61-3.55 (m, 1H), 3.31 (t, 2H, J=8.7 Hz), 3.24, 3.10 (AB_(q),2H, J=14.2 Hz), 3.00 (t, 1H, J=7.9 Hz), 2.21-2.14 (m, 1H), 1.87-1.78 (m,1H), 1.38 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 691 (M+H)⁺.R_(f)=0.49 in 50% acetone in hexanes.

Step B 2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester

Trifluoroacetic acid (60 mL) is added dropwise to a solution of3-(4-{2-[3-(4-Methoxy-benzyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (3.46 g, 5.0 lmmol) and triethylsilane (1.6 mL, 10.0mmol, d=0.728). The reaction mixture is stirred at ambient temperaturefor 2 hours, concentrated, and diluted with ethyl acetate. The solutionis washed with a saturated solution of aqueous sodium bicarbonate,water, and brine, then dried over Na₂SO₄, and concentrated in vacuo toprovide the title compound. ¹H NMR (400 MHz, CDCl₃): δ 7.58 (d, 2H,J=8.2 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.23-7.14 (m, 4H), 6.97 (t, 1H, J=7.4Hz), 6.82 (d, 2H, J=7.4 Hz), 6.78-(d, 2H, J=7.4 Hz), 4.44, 4.38 (AB_(q),2H, J=15.6 Hz), 4.20 (q, 2H, J=7.4 Hz), 4.07-3.99 (m, 2H), 3.96-3.89 (m,1H), 3.47 (t, 1H, J=8.2 Hz), 3.27, 3.09 (AB_(q), 2H, J=14.1 Hz), 3.04,3.02 (ABq, 1H, J=6.7 Hz), 2.08-1.99 (m, 1H), 1.98-1.92 (m, 1H), 1.38 (s,3H), 1.21 (t, 3H, J=6.7 Hz). MS [EI+] 571 (M+H)⁺, [El-] 569 (M−H)⁺.R_(f)=0.07 in 33% acetone in hexanes.

Step C 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acidethyl ester

A slurry of2-Methyl-3-(4-{2-[2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester (0.544 g, 0.953 mmol) and sodium hydride (0.042 g, 1.05mmol, 60% dispersion on mineral oil) in DMF (10 mL) was stirred for 1 h,then cooled to 0° C. Iodomethane (0.60 mL, 9.53 mmol, d=2.28) was added,then the reaction mixture is stirred 18 hours at ambient temperature anddiluted with ethyl acetate. The organic layer is washed, dried,concentrated, and purified by flash chromatography to provide the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, 2H, J=8.0 Hz), 7.37 (d,2H, J=8.0 Hz), 7.26-7.19 (m, 2H), 7.15 (d, 2H, J=8.9 Hz), 6.97 (t, 1H,J=8.0 Hz), 6.82 (d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.9 Hz), 4.46, 4.38(AB_(q), 2H, J=15.1 Hz), 4.20 (q, 2H, J=7.1 Hz), 3.97 (t, 2H, J=7.1 Hz),3.67-3.59 (m, 1H), 3.78 (t, 1H, J=8.9 Hz), 3.26, 3.10 (AB_(q), 2H,J=14.2 Hz), 2.99 (t, 1H, J=8.9 Hz), 2.85 (s, 3H), 2.28-2.21 (m, 1H),1.93-1.84 (m, 1H), 1.39 (s, 3H), 1.21 (t, 3H, J=7.1 Hz). MS [EI+] 585(M+H)⁺. R_(f)=0.35 in 50% acetone in hexanes.

Step D 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

A solution of2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester and 5N NaOH (0.7 mL) in ethanol (6 mL) is refluxed for1 h, cooled to ambient temperature, and concentrated in vacuo. Theresidue is diluted with CH₂Cl₂, washed, dried, and concentrated toprovide the title compound (0.186 g, 100%). ¹H NMR (400 MHz, CDCl₃): δ7.54 (d, 2H, J=8.3 Hz), 7.35 (d, 2H, J=8.3 Hz), 7.24-7.17 (m, 4H), 7.00(t, 1H, J=7.4 Hz), 6.89 (d, 2H, J=7.4 Hz), 6.73 (d, 2H, J=8.3 Hz), 4.45,4.37 (ABq, 2H, J=15.7 Hz), 3.96 (t, 2H, J=5.5 Hz), 3.68-3.62 (m, 1H),3.38 (t, 1H, J=8.3 Hz), 3.32, 3.10 (AB_(q), 2H, J=12.9 Hz), 3.00 (t, 1H,J=8.3 Hz), 2.84 (s, 3H), 2.27-2.19 (m, 1H), 1.92-1.85 (m, 1H), 1.39 (s,3H). MS [EI+] 557 (M+H)⁺, [EI−] 555 (M−H)⁺.

Example 64 2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid Step A2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester

To a solution of 3-(4-Hydroxy-phenyl)-2,2-dimethyl- propionic acidmethyl ester (31 mg, 0.15 mmol) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl- benzyl)-imidazolidin-4-yl]-ethylester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs₂CO₃ (64 mg, 0.19mmol), and the mixture heated at 60° C. for 15 hours. The mixture iscooled, diluted with water (25 ml) and extracted with ethyl acetate(2×25 ml). The combined organic extracts were washed with brine (25 ml),dried (Na₂SO₄), and concentrated to an oil. Purification by flashchromatography on a Biotage silica cartridge (gradient elution, 2:1hexanes:ethyl acetate to 1:4 hexanes:ethyl acetate) produced an oil (69mg, 94%). MS [EI+] 493 (M+H)⁺. Structure confirmed by ¹H-NMR.

Step B 2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

To a solution of the ester obtained from Step A (66 mg, 0.13 mmol) inmethanol (1.5 ml) is added 5N NaOH (0.3 ml, 1.5 mmol), and the mixturestirred for 20 hours at ambient temperature. The mixture is poured into1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). Thecombined ethyl acetate extracts were washed with water, brine, dried(Na₂SO₄), and concentrated to a foam (62 mg, 97%. MS [EI+] 479 (M+H)⁺.Structure confirmed by ¹H-NMR.

Example 65 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid Step A

A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid, methyl ester(2.35 g, 13.7 mmol) in DMF (100 mL) is treated with p-methyl benzylbromide (2.90 g, 15.7 mmol), MgSO₄ (3.30 g, 27.4 mmol) and then K₂CO₃(3.77 g, 27.3 mmol). The resultant mixture is stirred under N₂ in an icebath for 30 minutes and then warmed to room temperature for 16 h. Thereaction mixture is then filtered, and then aqueous 1N HCl (150 mL) isadded to the filtrate. The filtrate is extracted with EtOAc and theorganic layer dried. The solvent is removed to give 4.11 g crude productwhich is purified by flash chromatography using 100% CH₂Cl₂ then97.5:2.5 CH₂Cl₂:MeOH to give 3.67 g (97%) [1-(4-methyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. ¹H NMR.MS (ES⁺) Calc'd for C₁₄H₁₇N₂O₄ (M+1) 277. Found m/z 277 (100%).

Step B

A 0° C. solution of compound[1-(4-methyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methylester (1.60 g, 5.8 mmol) in DMF (28 mL) is treated with sodium hydride(60% dispersion, 0.25 g, 6.4 mmol) and warmed to room temperature andstirred under N₂ for 15 minutes. The resultant mixture is cooled to 0°C. and then treated with 1-propyl iodide (1.08 g, 6.4 mmol) and thenwarmed to room temperature and stirred for 30 minutes. The reaction isquenched with aqueous 1 N HCl (28 mL) and then worked up extractivelywith EtOAc and water. The organic layer is dried i and the solventremoved to give crude product that is purified by flash chromatographyusing a gradient of 10:1 to 1:1 hexanes:EtOAc to afford 1.40 g (76%)[1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acidmethyl ester. ¹H NMR. MS (ES⁺) Calc'd for C₁₇H₂₃N₂O₄ (M+1) 319. Foundm/z 319 (100%).

Step C

A solution of [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid methyl ester (1.67 g, 5.20 mmol) inmethanol (40 mL) is treated with aqueous 5 N NaOH (4.4 mL) and heated toreflux 1.5 hour. The reaction mixture is cooled, the solvent removed.The resultant residue is acidified and extracted with EtOAc. The organiclayer is dried and dried to afford 1.56 g (98%)[1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid.¹H NMR. MS (ES⁻) Calc'd for C₁₆H₁₉N₂O₄ (M−1) 303. Found m/z 303 (100%).

Step D

A solution of [1-(4-methyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-acetic acid (3.23 g, 10.6 mmol) in THF (50 mL) istreated dropwise with 1 M solution of borane-THF complex in THF (53.1mL, 53.1 mmol) and then stirred at room temperature under N₂ for 4hours. The reaction is quenched with methanol (30 mL) and stirred atroom temperature for 16 hour. The solvent is removed to give crudeproduct that is purified by flash chromatography using 97.5/2.5CH₂Cl₂:MeOH to afford 2.46 g (84%) 4-(2-hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one. ¹H NMR. MS (ES⁺) Calc'd forC₁₆H₂₅N₂O₂ (M+1) 277. Found m/z 277 (100%).

Step E

A solution of4-(2-hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one(2.46 g, 8.90 mmol), pyridine (2.46 g, 31.1 mmol) and 4-dimethyl aminopyridine (0.33 g, 2.70 mmol) in CH₂Cl₂ is treated with p-toluenesulfonicanhydride (4.65 g, 14.2 mmol) and the reaction stirred at roomtemperature for under N₂ for 1.5 hours. The reaction mixture is washedwith aqueous 0.5 N HCl (100 mL), the organic layer is dried, and thesolvent removed to afford crude product that is purified by flashchromatography using 100% CH₂Cl₂ then 97.5:2.5 CH₂Cl₂:MeOH to afford3.31 g (86%) toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethyl ester. ¹HNMR. MS (ES⁺) Calc'd for C₂₃H₃₁N₂O₄ (M+1) 431. Found m/z 431 (100%).

Step F

A mixture of 3-(4-hydroxy-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester (0.80 g, 2.66 mmol), toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl- imidazolidin-4-yl]-ethyl ester(1.26 g, 2.93 mmol) and Cs₂CO₃ (1.04 g, 3.19 mmol) in DMF (40 mL) isheated to 55° C. under N₂ for 17 h. The reaction is cooled and quenchedwith 1 N HCl (20 mL) and worked up extractively with Et₂O and water. Theorganic layer is dried and the solvent removed to afford crude productthat is purified by flash chromatography using 7:1 hexanes:acetone toafford 1.02 g (68%)2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester.The diasteriomeric products were separated by chiral HPLC (90:10heptane:IPA, 280 mL/min, 220 nm,) to give products in >99% de.R_(f)=0.49 (1:1 acetone:hexanes). ¹H NMR. MS (ES⁺) Calc'd for C₃₄H₄₃N₂O₅(M+1) 559. Found m/z 559 (100%).

Step G

A solution of2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester (0.456 g, 0.816 mmol) in ethanol (20 mL) istreated with aqueous 5 N NaOH (2 mL) and heated to reflux 1 h. Thereaction mixture is cooled, the solvent removed. The resultant residueis acidified and extracted with CH₂Cl₂. The organic layer is dried andthe solvent removed to afford 0.419 g (97%)2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₂H₃₉N₂O₅ (M+1)531.2859. Found m/z 531.2866.

Example 66 Preparation of2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid Step A

A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester(6.48 g, 37.6 mmol) in DMF (250 mL) is treated with2-(bromomethyl)-napthalene (9.15 g, 41.4 mmol), MgSO₄ (4.53 g, 37.6mmol) and then K₂CO₃ (15.61 g, 0.113 mol) at 0° C. The resultant mixtureis warmed to room temperature and stirred under N₂ for 16 hours. Thereaction mixture is filtered, and then aqueous 1N HCl (300 mL) is addedto the filtrate. The filtrate is extracted with Et₂O and the organiclayer dried. The solvent is removed to give a crude oil which ispurified by flash chromatography using 2:1 hexanes:acetone to afford6.27 g of (1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl)-aceticacid methyl ester (53%). R_(f)=0.32 (1:1 hexanes:acetone). ¹H NMR.

Step B

A 0° C. solution of compound(1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl)-acetic acid methylester (6.29 g, 20.1 mmol) in DMF (60 mL) is treated with sodium hydride(60% dispersion, 0.97 g, 24.3 mmol) and warmed to room temperature andstirred under N₂ for 20 minutes. The resultant mixture is cooled to 0°C. and then treated with 4-methoxybenzyl, chloride (6.35 g, 40.6 mmol)and then warmed to room temperature and stirred for 16 hours. Thereaction is quenched with aqueous 1 N HCl (100 mL) and then worked upextractively with Et₂O and water. The organic layer is dried and thesolvent removed to give crude product that is purified by flashchromatography using a gradient of 4:1 hexanes:acetone to afford 8.31 g(95%) [3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl]-acetic acidmethyl ester. R_(f)=0.44 (1:1 hexanes:acetone). ¹H NMR.

Step C

A solution of[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl]-aceticacid methyl ester (8.31 g, 19.2 mmol) in methanol (100 mL) is treatedwith aqueous 5 N NaOH (40 mL) and heated to reflux 1 hour. The reactionmixture is cooled, the solvent removed in vacuo. The resultant residueis acidified with aqueous 1 N HCl (300 mL) and extracted with Et₂O andwater. The organic layer is dried and the solvent removed in vacuo toafford 8.08 g (100%) acid that is utilized without purification. Asolution of crude acid (8.08 g, assume 19.2 mmol) in THF (100 mL) istreated dropwise with 1 M solution of borane-THF complex in THF (116.0mL, 0.116 mol) and then stirred at room temperature under N₂ for 16hours. The reaction is quenched with methanol (100 mL) and stirred atroom temperature for 1 hour. The solvent is removed to give crudeproduct that is purified by flash chromatography using a gradient of 3:1to 2:1 hexanes:acetone to afford 5.10 g (68%)4-(2-hydroxy-ethyl)-3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-imidazolidin-2-one.¹H NMR. MS (ES⁺) Calc'd for C₂₄H₂₇N₂O₃ (M+1) 391. Found m/z 391 (100%).

Step D

A solution of4-(2-hydroxy-ethyl)-3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-imidazolidin-2-one(5.10 g, 13.1 mmol), pyridine (3.62 g, 45.7 mmol) and 4-dimethyl aminopyridine (0.48 g, 3.92 mmol) in CH₂Cl₂ (100 mL) is treated withp-toluenesulfonic anhydride (6.82 g, 20.9 mmol) and the reaction stirredat room temperature for under N₂ for 1.5 h. The reaction mixture iswashed with aqueous 1 N HCl (100 mL), the organic layer was dried, andthe solvent removed in vacuo to afford crude product that is purified byflash chromatography using 3:1 hexanes:acetone to afford 6.74 g (95%)toluene-4-sulfonic acid2-[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethylester ¹H NMR. MS (ES⁺) Calc'd for C₃₁H₃₃N₂O₅ (M+1) 545. Found m/z 545(100%).

Step E

A mixture of 3-(4-hydroxy-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester (0.231 g, 0.735 mmol),2-[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethylester (1.74 g, 3.19 mmol) and Cs₂CO₃ (1.14 g, 3.5 mmol) in DMF (40 mL)is heated to 65° C. under N₂ for 17 h. The reaction is cooled andquenched with 1 N HCl (10 mL) and worked up extractively with Et₂O andwater. The organic layer is dried and the solvent removed to affordcrude product that is purified by flash chromatography using 8:1 then7:1 hexanes:acetone to afford 1.53 g (78%)3-(4-{2-[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester. R_(f)=0.43 (1:1 acetone:hexanes). ¹H NMR. MS (ES⁺) Calc'dfor C₄₂H₄₅N₂O₆ (M +1) 673. Found m/z 673 (100%).

Step F

A solution of3-(4-{2-[3-(4-methoxy-benzyl)-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester (1.54 g, 2.29 mmol) and triethylsilane (0.53 g, 4.56mmol) in trifluroacetic acid (40 mL) is stirred at room temperatureunder N₂ for 4 hours. The reaction mixture is diluted with water andextracted with EtOAc. The organic layer is dried and the solvent removedin vacuo to afford crude product that is purified by flashchromatography using 3:1 then 1:1 hexanes:acetone to afford 1.25 g(100%)2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy)-phenyl}-2-phenoxy-propionic acid ethyl ester. The diastereomeric mixturecould be separated by chiral HPLC (2:3 IPA:heptane mobile phase, 14mL/min, 225 nm) to afford >99% de2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethylesters. R_(f)=0.19 (1:1 acetone:hexanes). ¹H NMR. MS (ES⁺) Calc'd forC₃₄H₃₇N₂O₅ (M+1) 553. Found m/z 553 (100%).

Step G

A solution of a diasteriomeric mixture of2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (0.275 g, 0.498 mmol) in DMF (7 mL) is treated with NaH(60% oil suspension, 0.030 g, 0.750 mmol) and stirred at roomtemperature under N₂ for 30 minutes. The reaction is cooled to 0° C. andtreated with iodomethane (0.141 g, 0.996 mmol) and then warmed to roomtemperature and stirred for 3 hours. The reaction is quenched with 1 NHCl (5 mL) and worked up extractively with Et₂O and water. The organiclayer is dried and the solvent removed in vacuo to afford crude productthat is purified by flash chromatography using 4:1 hexanes:acetone toafford 0.268 g (95%)2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester. The diasteriomericproducts are separated by chiral HPLC (8×32 cm Chiralpak AD, 100% IPA,350 mL/min, 270 nm, to give products in>99% de ¹H NMR. R_(f)=0.35 (1:1acetone:hexanes). MS (ES⁺) Calc'd for C₃₅H₃₉N₂O₅ (M+1) 567. Found m/z567 (100%).

Step H

A solution of2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (0.161 g, 0.284 mmol) in ethanol (8 mL) is treated withaqueous 5 N NaOH (0.75 mL) and heated to reflux 1 h. The reactionmixture is cooled, the solvent removed in vacuo. The resultant residueis acidified with aqueous 1 N HCl (10 mL) and extracted with CH₂Cl₂. Theorganic layer is dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.113 g (74%)2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl]-ethoxy-phenyl}-2-phenoxy-propionic acid. ¹H NMR. HRMS (ES⁺) m/z exactmass calc'd for C₃₃H₃₅N₂O₅ (M+1) 539.2546. Found m/z 539.2548.

Example 67 2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid

A solution of2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl esters (0.021 g, 0.040 mmol) in ethanol (8 mL) wastreated with aqueous 5 N NaOH (1 mL) and heated to reflux 1 h. Thereaction mixture was cooled, the solvent removed in vacuo. The resultantresidue was acidified with aqueous 1 N HCl (10 mL) and extracted withCH₂Cl₂. The organic layer was dried (Na₂SO₄) and the solvent removed invacuo to afford 0.021 g (100%)2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₂H₃₃N₂O₅ (M+1)525.2389. Found m/z 525.2382.

Example 683-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid Step A

A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester(0.40 g, 0.94 mmol) in DMF (10 mL) is treated with NaH (60% oilsuspension, 0.094 g, 2.35 mmol) and stirred at room temperature under N₂for 30 minutes. The reaction is cooled to 0° C. and treated withtetrabutylammonium iodide (0.040 g, 0.11 mmol) and 3-methoxybenzylbromide (0.29 g, 1.43 mmol) and then warmed to room temperature andstirred for 1.5 h. The reaction is quenched with 1 N HCl (15 mL) andworked up extractively with Et₂O and water. The organic layer is dried(MgSO₄) and the solvent removed in vacuo to afford crude product that ispurified by flash chromatography using 2:1 hexanes:acetone to afford0.28 g (55%)3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester. ¹H NMR. R_(f)=0.41 (1:1 acetone:hexanes). MS (ES⁺)Calc'd for C₃₂H₃₉N₂O₆ (M+1) 547. Found m/z 547 (100%).

Step B

A solution of3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.28 g, 0.51 mmol) in ethanol (20 mL) istreated with aqueous 5 N NaOH (2 mL) and heated to reflux 1 h. Thereaction mixture is cooled, the solvent removed in vacuo. The resultantresidue is acidified with aqueous 1 N HCl (20 mL) and extracted withCH₂Cl₂. The organic layer is dried (Na₂SO₄) and the solvent removed invacuo to afford 0.257 g (97%)3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ¹H NMR (500 MHz, CDCl₃) [17.28-7.20 (m, 3H), 7.18 (d, 2H, J=8.80Hz), 7.04 (t, 1H, J=7.34 Hz), 6.91 (d, 2H, J=7.83 Hz), 6.82 (t, 1H, J7.83 Hz), 6.79-6.78 (m, 2H), 6.73 (d, 2H, J=8.83 Hz), 4.38, 4.28(AB_(q), 2H, J=14.92 Hz), 3.95 (t, 2H, J=5.87 Hz), 3.77 (s, 3H), 3.60(ddd, 1H, J=12.2 Hz, J=8.40 Hz, J=3.42 Hz), 3.36 (t, 1H, J=7.83 Hz),3.30, 3.10 (AB_(q), 2H, J=13.69 Hz), 2.96 (t, 1H, J=7.83 Hz), 2.83 (s,3H), 2.25-2.18 (m, 1H), 1.92-1.84 (m, 1H), 1.42 (s, 3H). HRMS (ES⁺) m/zexact mass calc'd for C₃₀H₃₅N₂O₆ (M+1) 519.2495. Found m/z 519.2504.

Example 69 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(2-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester(0.109 g, 0.255 mmol) in DMF (7 mL) is treated with NaH (60% oilsuspension, 0.021 g, 0.525 mmol) and stirred at room temperature underN₂ for 20 minutes. The reaction is treated with 2-trifluoromethyl benzylbromide (0.092 g, 0.385 mmol) and then warmed to room temperature andstirred for 3 hours. The reaction is quenched with acid and worked upextractively with Et₂O and water. The organic layer is dried and thesolvent removed to afford crude product that is dissolved in ethanol (20mL) is treated with aqueous 5 N NaOH (1.5 mL) and heated to reflux 1hour. The reaction mixture is cooled, the solvent removed. The resultantresidue is acidified with aqueous 1 N HCl (20 mL) and extracted withCH₂Cl₂. The organic layer is dried and the solvent removed in vacuo toafford crude acid that is purified by preparative HPLC to give 0.096 g(68%) of 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(2-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ¹H NMR. HRMS(ES⁺) m/z exact mass calc'd for C₃₀H₃₂N₂O₅F₃ (M +1) 557.2263. Found m/z557.2274.

Example 703-(4-{2-[1-(2-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid

A solution of 2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester(0.12 g, 0.281 mmol) in DMF (7 mL) is treated with NaH (60% oilsuspension, 0.023 g, 0.575 mmol) and stirred at room temperature underN₂ for 20 minutes. The reaction is treated with 2-methoxybenzyl chloride(0.066 g, 0.421 mmol) and then warmed to room temperature and stirredfor 3 h. The reaction is quenched with 1 N HCl (10 mL) and worked upextractively with Et₂O and water. The organic layer is dried (MgSO₄) andthe solvent removed in vacuo to afford crude product that is dissolvedin ethanol (20 mL) is treated with aqueous 5 N NaOH (1.5 mL) and heatedto ref lux 1 h. The reaction mixture is cooled, the solvent removed invacuo. The resultant residue is acidified with aqueous 1 N HCl (20 mL)and extracted with CH₂Cl₂. The organic layer is dried (Na₂SO₄) and thesolvent removed in vacuo to afford crude acid that is purified bypreparative HPLC to give 0.077 g (53%) of3-(4-{2-[1-(2-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₀H₃₅N₂O₆(M+1) 519.2495. Found m/z 519.2515.

Example 71

2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

To a mixture of 54 mg of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester in 2 mL of dry DMF at 0° C. under an atmosphere ofnitrogen, 10 mg of NaH (0.253 mmol) is added. The resulting solution isallowed to stand at ambient temperature for 20 min. Then 61 mg of4-trifluoromethylbenzyl bromide is added and resulting mixture isallowed to stand at ambient temperature for overnight. Reaction mixtureis diluted with Et₂O and 1N HCl. Organic layer is then washed with 1NHCl (2×10 mL), brine (2×10 mL), dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude material is in 5 mL of EtOH and 0.3mL of 5N NaOH. The mixture is heated to reflux for 1 h. The organicsolvent is then removed under vacuum and residue is dissolved in CH₂Cl₂and 1N HCl. Aqueous layer is washed with CH₂Cl₂ (2×10 mL). Combinedorganic layer is dried over Na₂SO₄, filtered and concentrated undervacuum. The crude material is purified by MS/LC to give 35 mg (49%) ofthe title product. ¹H NMR (400 MHz, CDCl₃): δ 7.56 (d, 2H, J=8.0 Hz),7.35 (d, 2H, J=8.0 Hz), 7.28-7.18 (m, 4H), 7.05 (t, 1H, J=7.2 Hz), 6.91(d, 2H, J=8.0 Hz), 6.74 (d, 2H, J=8.0 Hz), 5.49 (bs, 1H), 4.45, 4.39(AB_(q), 2H, J=15.4 Hz), 3.98 (t, 2H, J=5.8 Hz), 3.77-3.65 (m, 1H), 3.42(t, 1H, J=8.5 Hz), 3.28, 3.14 (AB_(q), 2H, J=14.0 Hz), 3.05 (t, 1H,J=8.5 Hz), 2.86 (s, 3H), 2.28-2.20 (m, 1H), 1.95-1.85 (m, 1H), 1.43 (s,3H). HRMS (ES⁺) m/z exact mass calcd for C₃₀H₃₂N₂O₅F₃ (m+1) 557.2263,found 557.2257.

Example 72 3-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-fluoro-phenoxy)-2-methyl-propionicacid

To a mixture of 80 mg of2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid ethyl ester in 5 mL of dry DMF at 0° C. under an atmosphere ofnitrogen, 18 mg of NaH (0.45 mmol) is added. The resulting solution isallowed to stand at r.t. for 20 min. Then 0.08 mL of 4-tert-butylbenzylbromide is added and resulting mixture is allowed to stand at r.t. forovernight. Reaction mixture is diluted with Et₂O and 1N HCl. Organiclayer is then washed with 1N HCl (2×10 mL), brine (2×10 mL), dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material is in5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture is heated to reflux for1 h. The organic solvent is then removed under vacuum and residue isdissolved in CH₂Cl₂ and 1N HCl. Aqueous layer is washed with CH₂Cl₂(2×10 mL). Combined organic layer is dried over Na₂SO₄, filtered andconcentrated under vacuum. The crude material is purified by MS/LC togive 45 mg (45%) of the title product. ¹H NMR (400 MHz, CDCl₃): δ 7.33(d, 2H, J=8.4 Hz), 7.18, 7.16 (ABq, 4H, J=8.6 Hz), 6.96-6.92 (m, 2H),6.88-6.85 (m, 2H), 6.77 (d, 2H, J=8.8 Hz), 4.38, 4.29 (AB_(q), 2H,J=14.8 Hz), 3.98 (t, 2H, J=6.0 Hz), 3.69 (bs, 1H), 3.73-3.66 (m, 1H),3.44 (t, 1H, J=8.6 Hz), 3.25, 3.11 (AB_(q), 2H, J=13.8 Hz), 3.06 (t, 1H,J=8.6 Hz), 2.86 (s, 3H), 2.28-2.19 (m, 1H), 1.97-1.89 (m, 1H), 1.38 (s,3H), 1.30 (s, 9H). HRMS (ES⁺) m/z exact mass calcd for C₃₃H₄₀N₂O₅F (m+1)563.2921, found 563.2917.

Example 73

2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid

To a mixture of 80 mg of2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under anatmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resultingsolution is allowed to stand at r.t. for 20 min. Then 99 mg of2-bromomethyl naphthalene is added and resulting mixture is allowed tostand at r.t. for overnight. Reaction mixture is diluted with Et₂O and1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture isheated to reflux for 1 h. The organic solvent is then removed undervacuum and residue is dissolved in CH₂Cl₂ and 1N HCl. Aqueous layer iswashed with CH₂Cl₂ (2×10 mL). Combined organic layer is dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material ispurified by MS/LC to give 51 mg (51%) of the title product. ¹H NMR (400MHz, CDCl₃): δ 7.82-7.79 (m, 3H), 7.67 (s, 1H), 7.50-7.44 (m, 2H), 7.35(d, 1H, J=8.4 Hz), 7.14 (d, 2H, J=8.6 Hz), 6.93 (t, 2H, J=8.4 Hz),6.87-6.83 (m, 2H), 6.71 (d, 2H, J=8.6 Hz), 5.11 (bs, 1H), 4.53 (s, 2H),3.95-3.90 (m, 2H), 3.85-3.70 (m, 1H), 3.46 (t, 1H, L=8.7 Hz), 3.23, 3.09(AB_(q), 2H, J=14.0 Hz), 3.07 (t, 1H, J=8.7 Hz), 2.89 (s, 3H), 2.26-2.18(m, 1H), 1.96-1.87 (m, 1H), 1.36 (s, 3H). HRMS (ES⁺) m/z exact masscalcd for C₃₃H₃₄N₂O₅F (m+1) 557.2452, found 557.2439.

Example 74 3-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-fluoro-phenoxy)-2-methyl-propionicacid

To a mixture of 80 mg of2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under anatmosphere of nitrogen, 18 mg of NaH (0.45 mmol) is added. The resultingsolution is allowed to stand at r.t. for 20 min. Then 0.07 mL of3,4-dimethylbenzyl chloride is added and resulting mixture is allowed tostand at r.t. for overnight. Reaction mixture is diluted with Et₂O and1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude material is in 5 mL of EtOH and 0.4 mL of 5N NaOH. The mixture isheated to reflux for 1 h. The organic solvent is then removed undervacuum and residue is dissolved in CH₂Cl₂ and 1N HCl. Aqueous layer iswashed with CH₂Cl₂ (2×10 mL). Combined organic layer is dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material ispurified by MS/LC to give 54 mg (56%) of the title product. ¹H NMR (400MHz, CDCl₃): δ 7.18 (d, 2H, J=8.4 Hz), 7.06 (d, 1H, J=7.6 Hz), 7.00 (s,1H), 6.97-6.85 (m, 5H), 6.75 (d, 2H, J=8.4 Hz), 4.34, 4.25 (AB_(q), 2H,J=15.0 Hz), 4.31 (bs, 1H), 3.98-3.90 (m, 2H), 3.69-3.61 (m, 1H), 3.39(t, 1H, J=8.7 Hz), 3.25, 3.11 (AB_(q), 2H, J=14.0 Hz), 3.00 (t, 1H,J=8.7 Hz), 2.84 (s, 3H), 2.29-2.17 (m, 1H), 2.22 (s, 6H), 1.94-1.87 (m,1H), 1.37 (s, 3H). HRMS (ES⁺) m/z exact mass calcd for C₃₁H₃₆N₂O₅F (m+1)535.2608, found 535.2614.

Example 75 3-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

To a mixture of 80 mg of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under anatmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resultingsolution is allowed to stand at r.t. for 20 minute Then 0.07 mL of4-tert-butylbenzyl bromide is added and resulting mixture is allowed tostand at r.t. for overnight. Reaction mixture is diluted with Et₂O and1N HCl. Organic layer is then washed with 1N HCl. (2×10 mL), brine (2×10mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture isheated to reflux for 1 h. The organic solvent is then removed undervacuum and residue is dissolved in CH₂Cl₂ and 1N HCl. Aqueous layer iswashed with CH₂Cl₂ (2×10 mL). Combined organic layer is dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material ispurified by MS/LC to give 40 mg (40%) of the title product. ¹H NMR (400MHz, CDCl₃): δ 7.51 (d, 2H, J=8.8 Hz), 7.38-7.32 (m, 2H), 7.16 (t, 4H,J=8.8 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.76 (d, 2H, J=8.8 Hz), 4.37, 4.28(AB_(q), 2H, J=14.8 Hz), 4.24 (bs, 1H), 3.97 (t, 2H, J=6.0 Hz),3.74-3.67 (m, 1H), 3.44 (t, 1H, J=9.2 Hz), 3.31, 3.16 (AB_(q), 2H,J=13.8 Hz), 3.07 (t, 1H, J=9.2 Hz), 2.85 (s, 3H), 2.27-2.18 (m, 1H),1.98-1.89 (m, 1H), 1.50 (s, 3H), 1.29 (s, 9H). HRMS (ES⁺) m/z exact masscalcd for C₃₄H₄₀N₂O₅F₃ (m+1) 613.2889, found 613.2872.

Example 762-Methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid

To a mixture of 80 mg of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under anatmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resultingsolution is allowed to stand at r.t. for 20 minute Then 89 mg of2-bromomethyl naphthalene is added and resulting mixture is allowed tostand at r.t. for overnight. Reaction mixture is diluted with Et₂O and1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture isheated to reflux for 1 h. The organic solvent is then removed undervacuum and residue is dissolved in CH₂Cl₂ and 1N HCl. Aqueous layer iswashed with CH₂Cl₂ (2×10 mL). Combined organic layer is dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material ispurified by MS/LC to give 51 mg (51%) of the title product. ¹H NMR (400MHz, CDCl₃): 7.81-7.77 (m, 3H), 7.66 (s, 1H), 7.48-7.45 (m, 4H), 7.35(dd, 1H, J=8.8, 1.6 Hz), 7.12 (d, 2H, J=8.8 Hz), 6.92 (d, 2H, J=8.4 Hz),6.69 (d, 2H, J=8.4 Hz), 6.20 (bs, 1H), 4.51 (s, 2H), 3.92-3.90 (m, 2H),3.72-3.64 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.29, 3.13 (AB_(q), 2H,J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.86 (s, 3H), 2.22-2.15 (m, 1H),1.93-1.84 (m, 1H), 1.46 (s, 3H). HRMS (ES⁺) m/z exact mass calcd forC₃₄H₃₄N₂O₅F₃ (m+1) 6072420, found 6072417.

Example 77 3-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid

To a mixture of 80 mg of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester in 5 mL of dry DMF at 0° C. under anatmosphere of nitrogen, 16 mg of NaH (0.40 mmol) is added. The resultingsolution is allowed to stand at r.t. for 20 min. Then 0.06 mL of3,4-dimethylbenzyl chloride is added and resulting mixture is allowed tostand at r.t. for overnight. Reaction mixture is diluted with Et₂O and1N HCl. Organic layer is then washed with 1N HCl (2×10 mL), brine (2×10mL), dried over Na₂SO₄, filtered and concentrated under vacuum. Thecrude material is in 5 mL of EtOH and 0.5 mL of 5N NaOH. The mixture isheated to reflux for 1 h. The organic solvent is then removed undervacuum and residue is dissolved in CH₂Cl₂ and 1N HCl. Aqueous layer iswashed with CH₂Cl₂ (2×10 ml). Combined organic layer is dried overNa₂SO₄, filtered and concentrated under vacuum. The crude material ispurified by MS/LC to give 54 mg (56%) of the title product. ¹H NMR (400MHz, CDCl₃): δ 7.51 (d, 2H, J=8.6 Hz), 7.16 (d, 1H, J=8.6 Hz), 7.10 (d,1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 6.99-6.94 (m, 3H), 6.75 (d, 2H,J=8.4 Hz), 4.33, 4.25 (AB_(q), 2H, J=14.8 Hz), 4.07 (bs, 1H), 3.97-3.93(m, 2H), 3.70-3.65 (m, 1H), 3.41 (t, 1H, J=8.8 Hz), 3.32, 3.16 (AB_(q),2H, J=13.8 Hz), 3.03 (t, 1H, J=8.8 Hz), 2.85 (s, 3H), 2.28-2.20 (m, 1H),2.22 (s, 3H), 1.96-1.88 (m, 1H), 1.50 (s, 3H). HRMS (ES⁺) m/z exact masscalcd for C₃₂H₃₆N₂O₅F₃ (m+1) 585.2576, found 585.2578.

Example 79 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-phenoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid

The titled compound is prepared, according to the proceduressubstantially as described herein, yield (0.192 g, 52%). Mass [EI+) 581(M+H)⁺, [El-] 579 (M−H)⁻.

Example 80 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl) -2-phenoxy- propionic acid

The titled compound is prepared, according to the proceduressubstantially as described herein, yield (0.127 g, 35%). Mass [EI+] 573(M+H)⁺, [EI−] 571 (M−H)⁻.

Example 81 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

The titled compound is prepared, according to the proceduressubstantially as described herein, yield (0.238 g, 63%). Mass [EI+] 573(M+H)⁺, [El-] 571 (M−H)⁻.

Example 822-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The titled compound is prepared, substantially according to theprocedures described herein to produce a white foamy solid (0.087 g,64%). Mass [EI+] 591 (M+H)⁺, [EI−] 589 (M- H)⁻.

Example 83 2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-1-(4-methyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The titled compound is prepared, substantially according to theprocedures described herein to produce a white foamy solid (0.022 g,18%). Mass [EI+] 521 (M+H)⁺, [EI−] 519 (M- H)⁻.

Example 84 3-(4-{2-[1-(3,4-Dichloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

The titled compound is prepared, substantially according to theprocedures described herein to produce a white foamy solid (0.107 g,80%). Mass [EI+] 574, 577 (M+H)⁺, [EI−] 573, 575 (M−H)⁻.

Example 85 3-(4-{2-[11-(3,4-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

The titled compound is prepared, substantially according to theprocedures described herein to produce a white foamy solid (0.107 g,84%). Mass [EI+] 543 (M+H)⁺, [EI−] 541 (M-H)⁻.

Example 86 3-(4-{2-[1-(3,5-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid

The titled compound is prepared, substantially according to theprocedures described herein to produce a white foamy solid (0.0824 g,65%). Mass [EI+] 543 (M+H)⁺, [EI−] 541 (M-H)⁻.

Example 872-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid

The titled compound is prepared, substantially according to theprocedures described herein to produce a white foamy solid (0.0753 g,58%). Mass [EI+] 543 (M+H)⁺, [EI−] 541 (M- H)⁻.

Example 883-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The title compound is prepares substantially according to the proceduresdescribed herein, and concentrated to an oil which is purified by MS/LCto yield an oil (25 mg, 25%). MS [EI+]565 (M+H)⁺. Structure confirmed by¹H-NMR.

Example 89 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

NaH (8.8 mg, 0.22 mmol, 60% w/w in mineral oil) is added to a cooled (0°C.) solution of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (78.5 mg, 0.18 mmol) in DMF (1 ml). After 5 minutes,the reaction mixture is removed from the cooling bath and stirred whilewarming to ambient temperature over one hour. After the solution iscooled again to 0° C., 4-(trifluoromethoxy)benzyl bromide (59 ul, 0.37mmol) is added in a single portion, the cooling bath removed, and themixture stirred for one hour. The reaction mixture is quenched with 1NHCl and extracted with ethyl acetate (2×). The organic extracts werewashed with water, brine, dried (Na₂SO₄), and concentrated to an oil.The crude product is dissolved in methanol (5 ml), treated with 5N NaOH(0.5 ml), and stirred for 14 hours at ambient temperature. Afterconcentration to remove methanol, the residue is partitioned betweendiethyl ether and water. The aqueous layer is adjusted to pH 2 withconc. HCl, then extracted with ethyl acetate (2×15 ml). The combinedethyl acetate extracts were washed with water, brine, dried (Na₂SO₄),and concentrated to an oil which is purified by MS/LC to yield an oil(33 mg, 31%). MS [EI+] 573 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 903-(4-{2-[1-(4-Fluoro-3-trifluoromethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid

NaH (9.2 mg, 0.23 mmol, 60% w/w in mineral oil) is added to a cooled (0°C.) solution of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (82.0 mg, 0.19 mmol) in DMF (1 ml). After 5 minutes,the reaction mixture is removed from the cooling bath and stirred whilewarming to ambient temperature over one hour. After the solution iscooled again to 0° C., 4-fluoro-3-(trifluoromethyl)benzyl bromide (148mg, 0.57 mmol) is added in a single portion, the cooling bath removed,and the mixture stirred for one hour. The reaction mixture is quenchedwith 1N HCl and extracted with ethyl acetate (2×). The organic extractswere washed with water, brine, dried (Na₂SO₄), and concentrated to anoil. The crude product is dissolved in methanol (5 ml), treated with 5NNaOH (0.5 ml), and stirred for 18 hours at ambient temperature. Afterconcentration to remove methanol, the residue is partitioned betweendiethyl ether and water. The aqueous layer is adjusted to pH 2 withconc. HCl, then extracted with ethyl acetate (2×15 ml). The combinedethyl acetate extracts were washed with water, brine, dried (Na₂SO₄),and concentrated to an oil which is purified by MS/LC to yield an oil(41 mg, 37%). MS [EI+] 575 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 913-(4-{2-[1-(3-Fluoro-4-trifluoromethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid

The title compound is prepared substantially as described herein andconcentrated to an oil which is purified by MS/LC to yield an oil (45mg, 41%). MS C EI+] 575 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 92 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acidStep A 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acidethyl ester

NaH (34 mg, 0.84 mmol, 60% w/w in mineral oil) is added to a cooled (0°C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester(300 mg, 0.70 mmol) in DMF (1.5 ml). After 5 minutes, the reactionmixture is removed from the cooling bath and stirred while warming toambient temperature over 1.5 hours. After the solution is cooled againto 0° C., 3-(trifluoromethyl)benzyl bromide (217 mg, 0.91 mmol) is addedin a single portion, the cooling bath removed, and the mixture stirredfor 2.5 hours. The reaction mixture is quenched with 1N HCl andextracted with ethyl acetate (2×). The organic extracts were washed withwater, brine, dried (Na₂SO₄), and concentrated to an oil. The crudeproduct is purified by flash chromatography on a Biotage silicacartridge (gradient elution, 5:1 hexanes:ethyl acetate to 1:1hexanes:ethyl acetate) to provide an oil (273 mg) which is a mixture ofthe title compound and corresponding substituted-benzyl ester as twoclosely eluting compounds. MS [EI+] 585 (M+H)⁺. Structure confirmed by¹H-NMR.

Step B 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

To a solution of the esters obtained from Step A (270 mg) in absoluteethanol (4.5 ml) is added 5N NaOH (1.9 ml, 9.5 mmol), and the mixturestirred for 20 hours at ambient temperature. The mixture is poured into1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethylacetate extracts were washed with water, brine, dried (Na₂SO₄), andconcentrated to an oil which is purified is purified by flashchromatography on a Biotage silica cartridge (gradient elution, 3:1hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate to yield a foam (78mg). MS [EI+]557 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 93 3-(4-{2-[1-(3,4-Dichloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

Step A 3-(4-{2-[1-(3,4-Dichloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester

NaH (34 mg, 0.84 mmol, 60% w/w in mineral oil) is added to a cooled (0°C.) solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester(300 mg, 0.70 mmol) in DMF (1.5 ml). After 5 minutes, the reactionmixture is removed from the cooling bath and stirred while warming toambient temperature over 1.5 hours. After the solution is cooled againto 0° C., 3,4-dichlorobenzyl bromide (218 mg, 0.91 mmol) is added in asingle portion, the cooling bath removed, and the mixture stirred for2.5 hours. The reaction mixture is quenched with 1N HCl and extractedwith ethyl acetate (2×). The organic extracts were washed with water,brine, dried (Na₂SO₄), and concentrated to an oil. The crude product ispurified by flash chromatography on a Biotage silica cartridge (gradientelution, 5:1 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) toprovide an oil (320 mg) which is a mixture of the title compound andcorresponding substituted-benzyl ester as two closely eluting compounds.MS [EI+] 586 (M+H)⁺. Structure confirmed by ¹H-NMR.

Step B 3-(4-{2-[1-(3,4-Dichloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

To a solution of the esters obtained from Step A (320 mg) in absoluteethanol (5.5 ml) is added 5N NaOH (2.2 ml, 10.9 mmol), and the mixturestirred for 20 hours at ambient temperature. The mixture is poured into1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethylacetate extracts were washed with water, brine, dried (Na₂SO₄), andconcentrated to an oil which is purified is purified by flashchromatography on a Biotage silica cartridge (gradient elution, 3:1hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate to yield a foam (180mg.) MS [EI+] 558 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 94 3-(4-{2-[1-(3,5-Bis-trifluoromethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

The title compound was prepared using substantially the proceduresdescribed herein.

Example 95 3-(4-{2-[1-(3,5-Bis-trifluoromethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acidStep A 3-(4-{2-[1-(3,5-Bis-trifluoromethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester

To a cooled (0° C.) suspension of NaH (41 mg, 1.03 mmol, 60% w/w inmineral oil) in DMF (1.0 ml) is added a solution of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (294 mg, 0.69 mmol) in DMF (1.5 ml). After 5 minutes,the reaction mixture is removed from the cooling bath and stirred whilewarming to ambient temperature over 45 minutes. After the solution iscooled again to 0° C., 3,5-Bis(trifluoromethyl)benzyl bromide (423 mg,1.38 mmol) is added in a single portion, the cooling bath removed, andthe mixture stirred for 1 hour. The reaction mixture is quenched with 1NHCl and extracted with ethyl acetate (2×). The organic extracts werewashed with water, brine, dried (Na₂SO₄), and concentrated to an oil.The crude product is purified by flash chromatography on a Biotagesilica cartridge (gradient elution, 5:1 hexanes:ethyl acetate to 1:1hexanes:ethyl acetate) to provide an oil (380 mg) which is a mixture ofthe title compound and corresponding substituted-benzyl ester as twoclosely eluting compounds. MS [EI+] 653 (M+H)⁺. Structure confirmed by¹H-NMR.

Step B 3-(4-{2-[1-(3,5-Bis-trifluoromethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

To a solution of the esters obtained from Step A (378 mg) in absoluteethanol (4 ml) is added 5N NaOH (1.5 ml, 7.5 mmol), and the mixturestirred for 20 hours at ambient temperature. The mixture is poured into1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethylacetate extracts were washed with water, brine, dried (Na₂SO₄), andconcentrated to an oil which is purified is purified by flashchromatography on a Biotage silica cartridge (gradient elution, 3:1hexanes:ethyl acetate to 1:2 hexanes:ethyl acetate to yield a foam (266mg.) MS [EI+] 625 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 963-(4-{2-[1-(4-Benzoyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid Step A3-(4-{2-[1-(4-Benzoyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid ethyl ester

To a cooled (0° C.) suspension of NaH (45 mg, 1.1 mmol, 60% w/w inmineral oil) in DMF (0.5 ml) is added a solution of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (320 mg, 0.75 mmol) in DMF (1.5 ml). After 5 minutes,the reaction mixture is removed from the cooling bath and stirred whilewarming to ambient temperature over 30 minutes. The solution is cooledagain to 0° C., and 4-(bromomethyl)benzophenone (188 mg, 0.68 mmol) isadded in a single portion, the cooling bath removed, and the mixturestirred for one hour. The reaction mixture is quenched with 1N HCl andextracted with ethyl acetate (2×). The organic extracts were washed withwater, brine, dried (Na₂SO₄), and concentrated to an oil. The crudeproduct is purified by flash chromatography on a Biotage silicacartridge (gradient elution, 2:1 hexanes:ethyl acetate to 1:2hexanes:ethyl acetate) to provide an oil (46 mg, 10%). MS [EI+] 621(M+H)⁺. Structure confirmed by ¹H-NMR.

Step B3-(4-{2-[1-(4-Benzoyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}1-phenyl)-2-methyl-2-phenoxy-propionicacid

To a solution of the ester obtained from Step A (46 mg, 0.1 mmol) inabsolute ethanol (2 ml) is added 5N NaOH (0.5 ml, 2.5 mmol), and themixture stirred for 14 hours at ambient temperature. The mixture ispoured into 1N HCl, then extracted with ethyl acetate (2×20 ml). Thecombined ethyl acetate extracts were washed with water, brine, dried(Na₂SO₄), and concentrated to an oil which is purified is purified byMS/LC to provide a oil (26 mg, 7%). MS [EI+] 593 (M+H)⁺. Structureconfirmed by ¹H-NMR.

Example 973-(4-{2-[1-(4-Isopropyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid

To a cooled (0° C.) suspension of NaH (24 mg, 0.60 mmol, 60% w/w inmineral oil) in DMF (1 ml) is added a solution of2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid ethyl ester (128 mg, 0.30 mmol) in DMF (1.5 ml). After 5 minutes,the reaction mixture is removed from the cooling bath and stirred whilewarming to ambient temperature over 45 minutes. After the solution iscooled again to 0° C., 4-isopropylbenzyl chloride (126 mg, 0.75 mmol) isadded in a single portion, the cooling bath removed, and the mixturestirred for 50 minutes. The reaction mixture is quenched with 1N HCl andextracted with ethyl acetate (2×). The organic extracts were washed withwater, brine, dried (Na₂SO₄), and concentrated to an oil. The crudeproduct is dissolved in ethanol (4 ml), treated with 5N NaOH (1.5 ml),and stirred for 24 hours at ambient temperature. The mixture is pouredinto 1N HCl, then extracted with ethyl acetate (2×20 ml). The combinedethyl acetate extracts were washed with water, brine, dried (Na₂SO₄),and concentrated to an oil which is purified by MS/LC to provide a foam(110 mg, 69%). MS [EI+] 531 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 982-Methyl-3-(4-{2-[3-methyl-1-(6-methyl-naphthalen-2-ylmethyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid

The title compound was prepared substantially as described herein andconcentrated to an oil which is purified by MS/LC to provide a whitesolid (83 mg, 50%). MS [EI+] 553 (M+H)⁺. Structure confirmed by ¹H-NMR.

To a solution of the ester obtained from Step A (69 mg, 0.1 mmol) inmethanol (2 ml) is added 5N NaOH (0.2 ml, 1 mmol), and the mixturestirred for 16 hours at ambient temperature. The mixture is poured into1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). Thecombined ethyl acetate extracts were washed with water, brine, dried(Na₂SO₄), and concentrated to a foam (62 mg, 100%). MS [EI+] 625 (M+H)⁺.Structure confirmed by ¹H-NMR.

Example 99 2-Methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid(diastereomer 4) Step A2-Methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acidethyl ester (diastereomer 4)

To a solution of 3-(3-Hydroxy-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester (Isomer 2) (43 mg, 0.143 mmol,) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (Isomer 2) (72 mg, 0.157 mmol) in DMF (1 ml) at 23° C. is addedCs₂CO₃ (61 mg, 0.186 mmol) and the suspension heated at 55° C. for 7hours. The mixture is cooled, filtered, and the filter cake washed withDMF (10 ml). The filtrate is poured into 1N HCl (35 ml) and extractedwith ethyl acetate (2×20 ml). The combined organic extracts were washedwith water (25 ml), brine (20 ml), dried (Na₂SO₄) and concentrated to anoil. Purification by flash chromatography on a Biotage silica cartridge(gradient elution, 4:1 hexanes:acetone to 1:1 hexanes:acetone) providedan oil, (72 mg, 87%) (diastereomer 4). MS [EI+] 585 (M+H)⁺. Structureconfirmed by ¹H-NMR.

Step B 2-Methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid(diastereomer 4)

To a solution of the ester obtained from Step A (72 mg, 0.12 mmol) inmethanol (2 ml) is added 5N NaOH (0.5 ml, 2.5 mmol), and the mixturestirred for 20 hours at ambient temperature. The mixture is poured into1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). Thecombined ethyl acetate extracts were washed with water, brine, dried(Na₂SO₄), and concentrated to an oil (64 mg, 94%) (diastereomer 4). MS[EI+] 557 (M+H)⁺. Structure confirmed by 1H-NMR.

Example 100 2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy- propionic acidStep A

A solution of crude 3-methyl-1-(4-trifluoromethyl-benzyl)-4-[2-(triphenyl-05-phosphanyl)-ethyl]-imidazolidin-2-one iodide(0.65 g, 0.964 mmol) in dry THF (4 mL) is treated with NaH (60% oilsuspension, 0.081 g, 2.02 mmol) and stirred at room temperature under N₂for 20 minutes to form the ylide. A solution of3-(4-formyl-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.21g, 0.672 mmol) in THF (4 mL) is then added to the ylide mixture dropwiseat room temperature and the reaction is stirred for 16 h. The reactionis diluted with Et₂O and washed with 1 N HCl and water. The organiclayer is dried (Na₂SO₄) and the solvent removed in vacuo to afford crudeproduct that is purified by flash chromatography using 6:1hexanes:acetone to afford 0.070 g (18%)2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propenyl}-phenyl)-2-phenoxy-propionicacid ethyl ester. R_(f)=0.22 (1:1 acetone:hexanes). ¹H NMR. MS (ES⁺)Calc'd for C₃₃H₃₆N₂O₄F₃ (M+1) 581. Found m/z 581 (100%).

Step B

A mixture of2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propenyl}-phenyl)-2-phenoxy-propionicacid ethyl ester (0.069 g, 0.119 mmol) and 10% Pd/C (70 mg) in EtOAc (50mL) is purged with N₂ then H₂ and then stirred under a H₂ balloon atroom temperature for 2 h. The reaction mixture is filtered through hyfloand the solvent removed in vacuo to afford 0.069 g (100%)2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionicacid ethyl ester. ¹H NMR. MS (ES⁺) Calc'd for C₃₃H₃₈N₂O₄F₃ (M+1) 583.Found m/z 583 (100%).

Step C

A solution of2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionicacid ethyl ester (0.062 g, 0.106 mmol) in ethanol (8 mL) is treated withaqueous 5 N NaOH (1 mL) and heated to reflux 1 h. The reaction mixtureis cooled, the solvent removed in vacuo. The resultant residue isacidified with aqueous 1 N HCl (20 mL) and extracted with CH₂Cl₂. Theorganic layer is dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.062 g (100%)2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₁H₃₄N₂O₄F₃ (M+1)555.2471. Found m/z 555.2459.

Example 1013-(2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid

Step A3-(2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid tert-butyl ester

To a solution of3-[2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-hydroxy-phenyl]-propionicacid tert-butyl ester (57 mg, 0.15 mmol) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs₂CO₃ (64 mg, 0.19mmol), and the mixture heated at 60° C. for 14 hours. The mixture iscooled, diluted with water (25 ml) and extracted with ethyl acetate(2×25 ml). The combined organic extracts were washed with brine (30 ml),dried (Na₂SO₄), and concentrated to an oil. Purification by flashchromatography on a Biotage silica cartridge (gradient elution, 5:1 to1:1 hexanes:acetone) produced an oil (72 mg, 73%). MS [EI+] 666 (M+H)⁺.Structure confirmed by HI-NMR.

Step B3-(2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid

A solution of the ester obtained in Step A (70 mg, 0.10 mmol) intrifluoroacetic (1 ml) and methylene chloride (2 ml) is stirred at 23°C. for 7 hours. Concentration of the reaction mixture gave an oil whichis partitioned between ethyl acetate (20 ml) and water (25 ml). Theethyl acetate layer is washed with water (15 ml), brine (20 ml), dried(Na₂SO₄), and concentrated to an oil which is purified by chromatographyon a Biotage silica cartridge (gradient elution, 100% methylene chlorideto 10:1 methylene chloride:methanol) to produce an oil (31 mg, 48%). MS[EI+] 610 (M+H)⁺. Structure confirmed by ¹H-NMR.

Example 102 2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

Step A 2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid methyl ester

To a solution of 3-(4-Hydroxy-phenyl)-2,2-dimethyl-propionic acid methylester (31 mg, 0.15 mmol) and Toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)- imidazolidin-4-yl]-ethylester (75 mg, 0.16 mmol) in DMF (1 ml) is added Cs₂CO₃ (64 mg, 0.19mmol), and the mixture heated at 60° C. for 15 hours. The mixture iscooled, diluted with water (25 ml) and extracted with ethyl acetate(2×25 ml). The combined organic extracts were washed with brine (25 ml),dried (Na₂SO₄), and concentrated to an oil. Purification by flashchromatography on a Biotage silica cartridge (gradient elution, 2:1hexanes:ethyl acetate to 1:4 hexanes:ethyl acetate) produced an oil (64mg, 88%). MS [EI+] 493 (M+H)⁺. Structure confirmed by ¹H-NMR.

Step B 2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

To a solution of the ester obtained from Step A (61 mg, 0.12 mmol) inmethanol (1.5 ml) is added 5N NaOH (0.3 ml, 1.5 mmol), and the mixturestirred for 20 hours at ambient temperature. The mixture is poured into1N HCl (20 ml), then extracted with ethyl acetate (2×15 ml). Thecombined ethyl acetate extracts were washed with water, brine, dried(Na₂SO₄), and concentrated to a foam (56 mg, 97%. MS [EI+] 479 (M+H)⁺.Structure confirmed by ¹H-NMR.

Example 103

Step A

The hydantoin from Example 13 (4.0 g, 16.1 mmol) and 3,4-dimethylbenzylchloride (2.5 ml, 17.7 mmol) were stirred together in DMF (100 ml).Potassium carbonate (8.9 g, 64.4 mmol) and magnesium sulfate (3.0 g,25.0 mmol) were added and the resulting mixture was heated to 45° C. for16 hrs under a drying tube. The reaction was cooled, added slowly to 1 Nhydrochloric acid (300 ml) and extracted twice with ethyl acetate. Theorganic layers were combined, washed with aqueous brine and dried oversodium sulfate. Evaporation of the solvent and subsequent purificationby flash chromatography (hexanes:ethyl acetate) gave the desiredalkylated hydantoin (1.6 g). C₂₂H₂₆N₂O₃ (MW=366.5); MS (M+, 367.3,M-365.4)

Step B

Sodium hydride (60% dispersion in mineral oil, 0.1 g, 2.4 mmol) wassuspended in DMF (25 ml) and cooled to 0° C. under a drying tube. Theproduct from Example 103, Step A (0.8 g, 2.2 mmol), dissolved in DMF (5ml), was added slowly and allowed to stir at 0° C. for 45 min.Iodopropane (0.23 ml, 2.4 mmol) added to the reaction and allowed tostir for 2.5 hrs. Hydrochloric acid (1N) added slowly, the reaction wasadded to water and extracted three times with ethyl acetate. The organiclayers were combined, washed with aqueous brine and dried over sodiumsulfate. Evaporation of the solvent and subsequent purification by flashchromatography (hexanes:ethyl acetate) gave the desired product (0.7 g).C₂₅H₃₂N₂O₃ (MW=408.6); MS (M+, 409.3)

Step C

Lithium aluminum hydride (0.084 g, 2.2 mmol) was suspended in THF (10ml) and cooled to 0° C. under a drying tube. The product from Example103, Step B (0.7 g, 1.7 mmol), dissolved in THF (5 ml), was added slowlyand stirred for 20 min. Hydrochloric acid (5N, 5 ml) added slowly andstirred for 30 min. The reaction mixture was added to water (40 ml) andextracted twice with ethyl acetate. The organic layers were combined,washed with aqueous brine then dried over sodium sulfate. Evaporation ofthe solvent and subsequent purification by flash chromatography(hexanes:ethyl acetate) gave the desired product (0.53 g). C₂₅H₃₂N₂O₂(MW=392.6); MS (M+, 393.2)

Step D

Boron tribromide was stirred in methylene chloride and cooled to 0° C.The product from Example 103, Step C (0.5 g, 1.3 mmol) was added andstirred for 30 min. Methanol (2 ml) slowly added and the mixture addedto water which was extracted twice with methylene chloride. The organiclayers were combined, washed with aqueous brine then dried over sodiumsulfate. Evaporation of the solvent gave the desired crude product (0.5g). C₂₄H₃₀N₂O₂ (MW=378.5); MS (M+, 379.3)

Step E

The product from Example 103, Step D (0.5 g, 1.3 mmol) and ethyl2-bromoisobutyrate (0.57 ml, 3.9 mmol) stirred together in ethanol (15ml). Potassium carbonate (powdered, Aldrich, 0.72 g, 5.2 mmol) andmagnesium sulfate (0.16 g, 1.3 mmol) added and the mixture was stirredat 60° C. overnight. The reaction mixture was cooled and carefully addedto 5 N hydrochloric acid (30 ml) and the resulting solution wasextracted twice with methylene chloride. The organic layers werecombined, washed with aqueous brine then dried over sodium sulfate.Evaporation of the solvent and subsequent purification by flashchromatography (hexanes:ethyl acetate) gave the desired product (0.48g). C₃₀H₄₀N₂O₄ (MW=492.7); MS (M+, 493.3)

Step F

The product from Example 103, Step E (0.45 g, 0.91 mmol) was dissolvedin dioxane (8 ml), lithium hydroxide (0.04 g, 1.8 mmol, in 2 ml water)added and stirred at ambient temperature overnight. The reaction wasadded to water and washed with ether. The aqueous layer was made acidicwith the addition of 5 N hydrochloric acid which was then extractedtwice with methylene chloride. These organic layers were combined,washed with aqueous brine and dried over sodium sulfate. Evaporation ofthe solvent and placement under a vacuum gave the desired product (0.37g) C₂₈H₃₆N₂O₄ (MW=464.6); MS (M+, 465.3, M-, 463.4)

Example 104

Step A

The hydantoin from Example 13 (3.0 g, 12.1 mmol) and p-tert- butylbenzylbromide (Aldrich, 2.4 ml, 13.3 mmol) were stirred together in DMF (75ml). Potassium carbonate (powdered, Aldrich, 6.7 g, 48.4 mmol) andmagnesium sulfate (1.8 g, 15.0 mmol) were added and the resultingmixture was heated to 50° C. for 4 hrs under a drying tube. The reactionwas cooled, added slowly to 5 N hydrochloric acid (100 mi) and extractedthree times with ethyl acetate. The organic layers were combined, washedwith aqueous brine and dried over sodium sulfate. Evaporation of thesolvent and subsequent purification by flash chromatography(hexanes:ethyl acetate) gave the desired alkylated hydantoin (2.8 g).C₂₄H₃₀ N₂O₃ (MW=394.5); MS (M+, 395.2, M−,393.3)

Step B

Sodium hydride (60% dispersion in mineral oil, 0.1 g, 2.5 mmol) wassuspended in DMF (25 ml) and cooled to 0° C. under a drying tube. Theproduct from Example 104, Step A (0.9 g, 2.3 mmol), dissolved in DMF (5ml), was added slowly and allowed to stir at 0° C. for 90 min.Iodomethane (0.15 ml, 2.5 mmol) added to the reaction and allowed tostir for 30 min. Hydrochloric acid (5N, 1 ml) added slowly to quench thereaction which was then added to water (75 ml) and extracted twice withethyl acetate. The organic layers were combined, washed with aqueousbrine then dried over sodium sulfate. Evaporation of the solvent andsubsequent purification by flash chromatography (hexanes:ethyl acetate)gave the desired product (0.82 g). C₂₅H₃₂N₂O₃ (MW=408.6); MS (M+, 409.2)

Step C

Following the procedure of Example 103, Step C, the product from Example104, Step B (0.82 g, 2.0 mmol) and lithium aluminum hydride (0.114 g,3.00 mmol) were used to yield the desired imidazolone as a crude product(0.61 g).

C₂₅H₃₂N₂O₂ (MW=392.6); MS (M+, 393.1)

Step D

The product from Example 104, Step C (0.6 g, 1.5 mmol) was stirred inmethylene chloride (10 ml) and boron tribromide (0.28 ml, 3.0 mmol)added via syringe. The mixture was stirred at ambient temperature for 30min. then quenched by the slow addition of methanol. The mixture wasadded to water (50 ml) and extracted twice with methylene chloride. Theorganic layers were combined, washed with aqueous brine and dried oversodium sulfate. Evaporation of the solvent gave the desired crudeproduct (0.51 g). C₂₄H₃₀N₂O₂ (MW=378.5); MS (M+, 379.2)

Step E

Following the procedure of Example 103, Step E, the product was fromExample 104, Step D (0.5 g, 1.3 mmol), ethyl 2-bromoisobutyrate (0.57ml, 3.9 mmol), potassium carbonate (powdered, Aldrich, 0.72 g, 5.2 mmol)and magnesium sulfate (0.16 g, 1.3 mmol) were used to yield the desiredproduct (0.13 g). C₃₀H₄₀N₂O₄ (MW=492.7); MS (M+, 493.3)

Step F

Following the procedure of Example 103, Step F, the product from Example104, Step E (0.12 g, 0.24 mmol) and lithium hydroxide (0.02 g, 0.72mmol) were used to yield the desired product after evaporation of thesolvent and placement under vacuum (0.089 g). C₂₈H₃₆N₂O₄ (MW=464.6); MS(M+, 465.1, M-, 463.2)

Example 105

Step A

Following the procedure of Example 104, Step B, the product from Example104, Step A (0.9 g, 2.3 mmol), sodium hydride (60% dispersion in mineraloil, 0.1 g, 2.5 mmol) and iodoethane (0.2 ml, 2.5 mmol) were used toyield the desired product (0.68 g). C₂₆H₃₄N₂O₃ (MW=422.6); MS (M+,423.2)

Step B

Following the procedure of Example 103, Step C, the product from Example105, Step A (0.68 g, 1.6 mmol) and lithium aluminum hydride (0.091 g,2.4 mmol) were used to yield the desired imidazolone as a crude product(0.6 g). C₂₆H₃₄N₂O₂ (MW=406.6); MS (M+, 407.1)

Step C

Following the procedure of Example 104, Step D, the product from Example105, Step B (0.6 g, 1.5 mmol) and boron tribromide (0.28 ml, 3.0 mmol)were used to yield the crude product (0.52 g). C₂₅H₃₂N₂O₂ (MW=392.6); MS(M+, 393.2)

Step D

Following the procedure of Example 103, Step E, the product from Example105, Step C (0.5 g, 1.3 mmol), ethyl 2-bromoisobutyrate (0.57 ml, 3.9mmol), potassium carbonate (powdered, Aldrich, 0.72 g, 5.2 mmol) andmagnesium sulfate (0.16 g, 1.3 mmol) were used to yield the product(0.31 g). C₃₁H₄₂N₂O₄ (MW=506.7); MS (M+, 507.1)

Step E

Following the procedure of Example 103, Step F, the product from Example105, Step D (0.30 g, 0.59 mmol) and lithium hydroxide (0.04 g, 1.7 mmol)were used to yield the desired product as a foam after evaporation ofthe solvent and placement under vacuum (0.244 g). C₂₉H₃₈N₂O₄ (MW=478.6);MS (M+, 479.1, M-, 477.2)

Example 106

Step A

Following the procedure of Example 104, Step B, the product from Example104, Step A (0.9 g, 2.3 mmol), sodium hydride dispersion in mineral oil,0.1 g, 2.5 mmol) and iodopropane (0.2 ml, 2.5 nmol) were used to yieldthe desired product (0.56 g). C₂₇H₃₆N₂O₃ (MW=436.6); MS (M+, 437.2)

Step B

Following the procedure of Example 103, Step C, the product from Example106, Step A (0.56 g, 1.3 mmol) and lithium aluminum hydride (Aldrich,0.076 g, 2.0 mmol) were used to yield the desired imidazolone as a crudeproduct (0.51 g). C₂₇H₃₆N₂O₂ (MW=420.6); MS (M+, 421.1)

Step C

Following the procedure of Example 104, Step D, the product from Example106, Step B (0.5 g, 1.2 mmol) and boron tribromide (0.23 ml, 2.4 mmol)were used to yield the crude product (0.45 g). C₂₆H₃₄N₂O₂ (MW=406.6); MS(M+, 407.3)

Step D

Following the procedure of Example 103, Step E, the product from Example106, Step C (0.45 g, 1.1 mmol), ethyl 2-bromoisobutyrate (0.57 ml, 3.9mmol), potassium carbonate (0.72 g, 5.2 mmol) and magnesium sulfate(0.16 g, 1.3 mmol) were used to yield the product (0.26 g). C₃₂H₄₄N₂O₄(MW=520.7); MS (M+, 521.3)

Step E

Following the procedure of Example 103, Step F, the product from Example106, Step D (0.26 g, 0.50 mmol) and lithium hydroxide (0.036 g, 1.5mmol) were used to yield the desired product after evaporation of thesolvent and placement under vacuum (0.184 g). C₃₀H₄₀N₂O₄ (MW 492.7); MS(M+, 493.3, M-, 491.4)

Example 107

Step A

The hydantoin from Example 17, Step A (490.6 mg, 0.988 mmol) wasdissolved in DMF (10 mL) and cooled to 0° C. under an atmosphere of N₂.The mixture was treated with NaH (60% dispersion in oil, 45.7 mg, 1.14mmol) and, after 30 minutes, n-propyl iodide (112 μL, 1.15 mmol). Thereaction mixture was warmed to room temperature, stirred for 1 hour,then poured into 1 N HCl (50 mL). The resulting solution was extractedwith ethyl acetate (2×50 mL). The combined organic extracts were driedover Na₂SO₄ and concentrated. Purification by chromatography (4:1hexanes:ethyl acetate) gave the desired product as a colorless oil(416.1 mg, 78%). C₃₁H₄₂N₂O₆ (MW=538.69); mass spectroscopy:(M+NH4+)=556.3

Step B

A CH₂Cl₂ solution (15 mL) of the ester from Step A (0.411 g, 0.764 mmol)was cooled to 0° C. and treated with TFA (2.0 mL, 26 mmol). The mixturewas warmed to room temperature and stirred for 3 hours. The solvent wasconcentrated to give the crude acid, which was used in the subsequentreaction without further purification. C₂₇H₃₄N₂O₆ (MW=482.58); massspectroscopy: (MH⁺)=483.2, (MH⁻)=481.3

Step C

The hydantoin from Step B was dissolved in ethanol (15 mL) and treatedwith NaBH₄ (331 mg, 8.8 mmol). Additional NaBH₄ was added to thereaction mixture after 5 hr (150 mg, 4.0 mmol). The resulting mixturewas stirred at room temperature overnight then quenched by the carefuladdition of 5 N HCl (5 mL). The mixture was stirred for 30 minutes thendiluted with additional 5 N HCl (50 mL) and extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄ and concentrated. Purification by chromatography (gradient:2:1 ethyl acetate:hexane to 100% ethyl acetate to 9:1 ethylacetate:methanol) gave the desired imidazolone as a white solid (237 mg,66% for two steps). C₂₇H₃₄N₂O₅ (MW=466.58); mass spectroscopy:(MH⁺)=467.3, (MH⁻)=465.3

Step A

The ester from Example 14, Step F (1.88 g, 0.0050 mol) was dissolved inDMF and treated with α-chloro-p-xylene (0.773 g, 0.0055 mol) andpowdered K₂CO₃. The resulting mixture was stirred at room temperatureovernight. The reaction mixture was poured into 1N HCl and combined withethyl acetate. The organic layer was extracted and washed with brinethen dried and concentrated. Purification of the crude material by flashchromatography (4:1 hexanes:ethyl acetate) yielded the desired hydantoin(2.10 g, 88%). C₂₈H₃₆N₂O₅ (MW=480.26); mass spectroscopy (MH⁺)=480.1

Step B

Sodium hydride (0.050 g, 0.0011 mol) was dissolved in DMF (5 ml) andcooled to OoC. The hydantoin from Step A (0.50 g, 0.0010 mol) was addedas a solution in DMF (10 ml). The mixture was stirred for ninetyminutes. Iodomethane (0.068 ml, 0.0011 mol) was added and the reactionwas stirred for thirty minutes. Hydrochloric acid was added to quenchthe reaction. The aqueous layer was extracted with ethyl acetate. Theorganic layer was concentrated. Purification of the resulting materialby flash chromatography (10:1 hexanes:ethyl acetate) gave the desiredhydantoin (0.247 g, 0.0010 mol). C₂₉H₃₈N₂O₀ (MW=494.28); massspectroscopy (MH⁺)=494.0

Step C

The hydantoin from Step B (0.247 g, 0.00050 mol) was dissolved inmethylene chloride (5 ml) and treated with trifluoro acetic acid (0.269ml, 0.0035 mol) and stirred overnight. The solvent was concentrated andthe product was vacuum dried. C₂₅H₃₀N₂O₅ (MW=438.22); mass spectroscopy(MH⁺)=439

Step D

The acid from Step C (0.289, 0.00066 mol) was dissolved in ethanol (10ml) and treated with sodium borohydride (0.249 g, 0.0066 mol). One hourlater, additional sodium borohydride (0.249 g) was added and thereaction was stirred overnight. On the next day, more sodium borohydride(0.249 g) was added to drive the reaction. The reaction was left tostir. On the fifth day, 5N HCl (50 ml) was added to the reaction mixturefollowed by water (50 ml). The aqueous solution was extracted with ethylacetate (2×, 50 ml). The organic layer was washed with brine, dried overNa₂SO₄, and concentrated. Purification by flash chromatography (100%ethyl acetate) gave the desired acid as a white solid (0.062 g, 23%)C₂₅H₃₀N₂O₄ (MW=422.53); mass spectroscopy (MH⁺)=423.2

Example 109

Step A

The hydantoin from Example 13 (1.0 g, 4.0 mmol),2-(chloromethyl)quinoline hydrochloride (0.9 g, 4.4 mmol) andtriethylamine (0.4 g, 4.0 mmol) were combined in DMF (25 ml). Potassiumcarbonate (2.2 g, 16.0 mmol) and magnesium sulfate (0.6 g, 5.0 mmol)added and the mixture was heated to 50° C., under a drying tube,overnight. The reaction mixture was added to hydrochloric acid (1N, 50ml) and extracted three times with methylene chloride. The organiclayers were combined, washed with aqueous brine then dried over sodiumsulfate. Evaporation of the solvent and washing with 7:3 hexane/ethylacetate yielded the desired product as a solid (0.8 g) C₂₃H₂₃N₃O₃(MW=389.5); MS (M+, 390.2)

Step B

Following the procedure of Example 104, Step B, the product from Example109, Step A (0.5 g, 1.3 mmol), sodium hydride (Aldrich, 60% dispersionin mineral oil, 0.06 g, 1.4 mmol) and iodopropane (Aldrich, 0.14 ml, 1.4mmol) were used to yield the desired product (0.41 g). C₂₆H₂₉N₃O₃(MW=431.5); MS (M+, 432.1)

Step C

Following the procedure of Example 103, Step C, the product from Example109, Step B (0.4 g, 0.93 mmol) and lithium aluminum hydride (0.05 g, 1.4mmol) were used to yield the desired imidazolone as a crude product(0.45 g). C₂₆H₂₉N₃O₂ (MW=415.5); MS (M+, 416.2)

Step D

Following the procedure of Example 104, Step D, the product from Example109, Step C (0.39 g, 0.93 mmol) and boron tribromide (0.19 ml, 2.0 mmol)were used to yield the crude product (0.47 g). C₂₅H₂₇N₃O₂ (MW=401.5); MS(M+, 402.2)

Step E

Following the procedure of Example 103, Step E, the product from Example109, Step D (0.37 g, 0.93 mmol), ethyl 2-bromoisobutyrate (0.48 ml, 3.3mmol), potassium carbonate (powdered, Aldrich, 0.58 g, 4.2 mmol) andmagnesium sulfate (0.18 g, 1.5 mmol) were used to yield the product(0.05 g). C₃₁H₃₇N₃O₄ (MW=515.7); MS (M+, 516.3)

Step F

Following the procedure of Example 103, Step F, the product from Example109, Step E (0.05 g, 0.1 mmol) and lithium hydroxide (0.07 g, 0.3 mmol)were used to yield the desired product (0.022 g). C₂₉H₃₃N₃O₄ (MW=487.6);MS (M+, 488.3, M-, 486.4)

Example 110

Step A

The methoxy ether from Example 13 (3.0 g, 0.012 mol) was dissolved inDMF and treated with p-methyl chlorobenzene (1.87 g, 0.013 mol) andpowdered K₂CO₃ (6.62 g, 0.048 mol). The resulting mixture was stirred atroom temperature overnight. The reaction mixture was poured into 1N HCland combined with ethyl acetate. The organic layer was extracted andwashed with brine then dried and concentrated. Purification of the crudematerial by flash chromatography (2:1 hexanes:ethyl acetate) yielded thedesired hydantoin (3.15 g, 75%). C₂₁H₂₄N₂O₃ (MW=352.18); massspectroscopy (MH⁺)=353

Step B

The hydantoin from Step A (0.750 g, 0.0021 mol) was dissolved in DMF (5ml) and treated with NaH (0.091 g, 0.0023 mol) followed by1-iodo-propane (0.228 ml, 0.0023 mol). The reaction was stirredovernight under nitrogen. The reaction mixture was poured into 1N HCland combined with ethyl acetate. The organic layer was extracted andwashed with brine then dried and concentrated. Purification of the crudematerial by flash chromatography (4:1 hexanes:ethyl acetate) yielded thedesired product (0.454 g, 55%). C₂₄H₃₀N₂O₃ (MW=394.52); massspectroscopy (MH⁺)=395.2

Step C

Lithium aluminum hydride (0.0651 g, 0.0017 mol) was dissolved in THF (5ml). A THF solution of the hydantoin from Step B was added. The reactionwas stirred overnight at room temperature. The reaction was quenched bythe addition of 5N HCl. After stirring for thirty minutes, water wasadded and the solution was extracted with ethyl acetate. The organiclayer was extracted and washed with brine then dried and concentrated.The crude product was carried forth without further purification (0.400g, 96%). C₂₄H₃₀N₂O₂ (MW =378.23); mass spectroscopy (MH⁺)=379.2

Step D

The methoxy ether from Step C (0.400 g, 0.001 mol) was dissolved inmethylene chloride (5 ml) and cooled to 0° C. To this solution wasadded, dropwise, a solution of BBr₃ (0.200 ml, 0.002 mol) in methylenechloride (5 ml). After stirring for about thirty minutes, the reactionmixture was cooled to 0° C. and quenched by the dropwise addition ofmethanol/methylene chloride. The solvent was concentrated and theresulting material was dissolved in methylene chloride. The organiclayer was extracted with water followed by brine. Upon evaporation ofthe solvent, the phenol (0.334 g, 92%) was obtained and was carriedforth without further purification. C₂₃H₂₈N₂O₂ (MW=364.22); massspectroscopy (MH⁺)=365.2

Step E

The phenol from Step D (0.334 g, 0.00092 mol) was dissolved in EtOH (5ml) and treated with ethyl 2-bromoisobutyrate (0.404 ml, 0.0028 mol),powdered K₂CO₃ (0.508 g, 0.0037 mol), and MgSO₄ (0.110 g, 0.00092 mol).The reaction was stirred overnight at 55° C. Upon cooling, the reactionmixture was poured into 5N HCl and combined with EtOAc. The organiclayer was extracted with water followed by brine then concentrated todryness. Purification by flashed chromatography (1:1 hexanes:ethylacetate) gave the ester (0.205 g, 46%). C₂₉H₃₈N₂O₄ (MW=478.28); massspectroscopy (MH⁺)=479.3

Step F

The ester from Step E (0.205 g, 0.00043 mol) was dissolved in methanol(4 ml) and treated with a solution of LiOH in water (1 ml). The reactionwas stirred overnight. The reaction was cooled and water (20 ml) wasadded to the solution. The solution was then acidified using 1N HCl topH=3 then extracted with ethyl acetate. The organic layer wasconcentrated to afford the desired carboxylic acid (0.128 g, 66%).C₂₇H₃₄N₂O₄ (MW=450.58); mass spectroscopy (MH⁺)=451.2

Example 111

Step A

The hydantoin from Example 110; Step A (0.748 g, 0.0021 mol) wasdissolved in DMF (5 ml) and treated with NaH (0.091 g, 0.0023 mol)followed by 1-iodo-hexane (0.339 ml, 0.0023 mol). The reaction wasstirred overnight under nitrogen. The reaction mixture was poured into1N HCl and combined with ethyl acetate. The organic layer was extractedand washed with brine then dried and concentrated. Purification of thecrude material by flash chromatography (5:1 hexanes:ethyl acetate)yielded the desired product (0.622 g, 68%). C₂₇H₃₂F₂N₂O₅ (MW=502.23);mass spectroscopy (MH⁺)=447.1

Step B

Lithium aluminum hydride (0.622 g, 0.0014 mol) was dissolved in THF (10ml). A THF solution of the hydantoin from Step A was added. The reactionwas stirred for thirty minutes at room temperature. The reaction wasquenched by the addition of 5N HCl. After stirring for thirty minutes,water was added and the solution was extracted with ethyl acetate. Theorganic layer was extracted and washed with brine then dried andconcentrated. The crude product was carried forth without furtherpurification (0.556 g, 95%). C₂₇H₃₂F₂N₂O₅ (MW =502.23); massspectroscopy (MH⁺)=447.1

Step C

The methoxy ether from Step B (0.556 g, 0.0013 mol) was dissolved inmethylene chloride (7 ml) and cooled to 0° C. To this solution wasadded, dropwise, a solution of BBr₃ (0.250 ml, 0.0026 mol) in methylenechloride (5 ml). After stirring for about twenty minutes, the reactionmixture was cooled to 0° C. and quenched by the dropwise addition ofmethanol/methylene chloride. The solvent was concentrated and theresulting material was dissolved in methylene chloride. The organiclayer was extracted with water followed by brine. Upon evaporation ofthe solvent, the phenol (0.465 g, 88%) was obtained and was carriedforth without further purification. C₂₂H₂₇N₃O₂ (MW=365.48); massspectroscopy (MH⁺)=366.3

Step D

The phenol from Step C (0.465 g, 0.0011 mol) was dissolved in EtOH (10ml) and treated with ethyl 2-bromoisobutyrate (0.504 ml, 0.0034 mol),powdered K₂CO₃ (0.607 g, 0.0044 mol), and MgSO₄ (0.132 g, 0.0011 mol).The reaction was stirred overnight at 55° C. Upon cooling, the reactionmixture was poured into 5N HCl and combined with EtOAc. The organiclayer was extracted with water followed by brine then concentrated todryness. Purification by flashed chromatography (3:1 hexanes:ethylacetate; 2:1 hexanes:ethyl acetate) gave the ester (0.241 g, 42%).C₂₈H₃₇N₃O₄ (MW 479.62); mass spectroscopy (MH⁺)=480.3

Step E

The ester from Step D (0.241 g, 0.00046 mol) was dissolved in methanol(4 ml) and treated with a solution of LiOH in water (1 ml). The reactionwas stirred overnight. The reaction was cooled and water (20 ml) wasadded to the solution. The solution was then acidified using 1N HCl topH=3 then extracted with ethyl acetate. The organic layer wasconcentrated to afford the desired carboxylic acid (0.089 g, 40%).C₂₆H₃₃N₃O₄ (MW=451.57); mass spectroscopy (MH⁺)=452.3

Example 112

Step A

A DMF solution (55 mL) of the hydantoin from Example 13(1.92 g, 7.73mmol) was treated sequentially with 2-bromomethyl-1-naphthalene (1.87 g,8.46 mmol), K₂CO₃ (2.2 g, 16 mmol), and MgSO₄ (2.3 g, 19 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction was quenched by the slow addition of 1 N HCl (150 mL). Theresulting mixture was extracted with ethyl acetate (2×100 mL). Thecombined organic extracts were washed with brine then dried over Na₂SO₄and concentrated. Purification by chromatography (gradient: 3:1 to 1:1hexanes:ethyl acetate) gave the desired alkylated hydantoin as a whitesolid (1.47 g, 49%). C₂₄H₂₄N₂O₃ (MW=388.47); mass spectroscopy:(MH⁺)=389.2, (MH⁻)=387.2

Step B

The hydantoin from Step A (637 mg, 1.64 mmol) was dissolved in DMF (20mL) and cooled to 0° C. under an atmosphere of N₂. The mixture wastreated with NaH (60% dispersion in oil, 76.3 mg, 1.91 mmol) and, after15 minutes, n-propyl iodide (192 μL, 1.97 mmol). The reaction mixturewas warmed to room temperature, stirred for 1 hour, then poured into 1 NHCl (100 mL). The resulting solution was extracted with ethyl acetate(2×75 mL). The combined organic extracts were dried over Na₂SO₄ andconcentrated. Purification by chromatography (4:1 hexanes:ethyl acetate)gave the desired product as a yellowish oil (693 mg, 98%). C₂₇H₃₀N₂O₃(MW=430.55); mass spectroscopy: (MH⁺)=431.2

Step C

To a slurry of LAH (99.3 mg, 2.6 mmol) in THF (10 mL) at 0° C. under N₂was added the hydantoin from Step B (0.693 g, 1.61 mmol) as a solutionin THF (10 mL). After 15 minutes the reaction was quenched by theaddition of 5 N HCl (5 mL) in THF (5 mL)., stirred for 30 minutes, thendiluted with H₂O (75 mL). The resulting mixture was extracted with ethylacetate (3×50 mL). The combined organic extracts were washed with brine,dried over Na₂SO₄ and concentrated to give the desired imidazolone. Thecrude product was carried forward without further purification.C₂₇H₃₀N₂O₂ (MW=414.55); mass spectroscopy: (MH⁺)=415.2

Step D

The imidazolone from Step C was dissolved in CH₂Cl₂ (15 mL) and cooledto 0° C. under an atmosphere of N₂. BBr₃ (475 μL, 5.0 mmol) was addeddropwise, then the reaction mixture was warmed to room temperature.After 1 hr, the solution was again cooled to 0° C. and quenched by theslow addition of a methanol (4 mL) solution in CH₂Cl₂ (12 mL). Theresulting mixture was extracted with H₂O (50 mL). The aqueous extractwas washed with CH₂Cl₂ (50 mL) then the combined organic extracts werewashed with brine, dried over Na₂SO₄, and concentrated to give thedesired phenol as an oil. The crude product was carried forward withoutfurther purification. C₂₆H₂₈N₂O₂ (MW=400.53); mass spectroscopy:(MH⁺)=401.2, (MH⁻)=399.3

Step E

An ethanol solution (15 mL) of the phenol from Step D was treatedsequentially with ethyl 2-bromoisobutyrate (900 μL, 6.6 mmol), K₂CO₃(1.0 g, 7.2 mmol), and MgSO₄ (1.0 g, 8.3 mmol). The resulting mixturewas heated to 55-65° C. overnight. The reaction was quenched by the slowaddition of 1 N HCl (5 mL) then poured into additional 1 N HCl (50 mL).The resulting mixture was extracted with CH₂Cl₂ (2×50 mL). The combinedorganic extracts were washed with brine then dried over Na₂SO₄ andconcentrated. Purification by chromatography (gradient: 2:1 to 1:1hexanes:ethyl acetate) gave the desired ester as a slightly yellow oil(536.4 mg, 65% for 3 steps). C₃₂H₃₈N₂O₄ (MW=514.67); mass spectroscopy:(MH⁺)=515.4

Step F

A dioxane solution (10 mL) of the ester from Step E (516.5 mg, 1.0 mmol)was treated with an aqueous solution (5 mL) of LiOH (88 mg, 3.7 mmol).The mixture was heated to 50° C. for 2 hr then the solvent wasconcentrated and the resulting oil diluted with H₂O (50 mL) andextracted with Et₂O (501 nL). The aqueous extract was acidified with 1 NHCl and extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, and concentrated togive the desired carboxylic acid as a slightly yellow foam-like solid(392.8 mg, 81%) C₃₀H₃₄N₂O₄ (MW=486.62); mass spectroscopy: (MH⁺)=487.2,(MH⁻)=485.4

Step A

The methoxy ether from Example 13 (1.0 g, 0.0040 mol) was dissolved inDMF and treated with 3, 5 difluoro bromobenezene (0.574 ml, 0.0044 mol)and powdered K₂CO₃ (2.20 g, 0.0080 mol). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto 1N HCl and combined with ethyl acetate. The organic layer wasextracted and washed with brine then dried and concentrated.Purification of the crude material by flash chromatography (4:1hexanes:ethyl acetate; 4:1 hexanes:ethyl acetate) yielded the desiredhydantoin (0.710 g, 46%). C₂₀H₂₀F₂N₂O₃ (MW=3664.14); mass spectroscopy(MH⁺)=375.1

Step B

The hydantoin from Step A (0.710 g, 0.0019 mol) was dissolved in DMF (10ml) and treated with NaH (0.084 g, 0.0021 mol) followed by1-iodo-propane (0.200 ml, 0.0021 mol). The reaction was stirredovernight under nitrogen. The reaction mixture was poured into 1N HCland combined with ethyl acetate. The organic layer was extracted andwashed with brine then dried and concentrated. Purification of the crudematerial by flash chromatography (2:1 hexanes:ethyl acetate) yielded thedesired product (0.742 g, 94%). C₂₃H₂₆F₂N₂O₃ (MW=416.19); massspectroscopy (MH⁺)=417

Step C

Lithium aluminum hydride (0.742 g, 0.0018 mol) was dissolved in THF (7ml). A THF solution of the hydantoin from Step B was added. The reactionwas stirred for ninety minutes at room temperature. The reaction wasquenched by the addition of 5N HCl. After stirring for thirty minutes,water was added and the solution was extracted with ethyl acetate. Theorganic layer was extracted and washed with brine then dried andconcentrated. The crude product was carried forth without furtherpurification (0.690 g, 96%). C₂₃H₂₆F₂N₂O₂ (MW =400.20); massspectroscopy (MH⁺)=401

Step D

The methoxy ether from Step C (0.690 g, 0.0017 mol) was dissolved inmethylene chloride and cooled to 0° C. To this solution was added,dropwise, a solution of BBr₃ (0.326 ml, 0.0035 mol) in methylenechloride. After stirring for about thirty minutes, the reaction mixturewas cooled to 0° C. and quenched by the dropwise addition ofmethanol/methylene chloride. The solvent was' concentrated and theresulting material was dissolved in methylene chloride. The organiclayer was extracted with water followed by brine. Upon evaporation ofthe solvent, the phenol (0.550 g, 84%) was obtained and was carriedforth without further purification. C₂₂H₂₄F₂N₂O₂ (MW=386.18); massspectroscopy (MH⁺)=387.2

Step E

The phenol from Step D (0.055 g, 0.0014 mol) was dissolved in EtOH (7ml) and treated with ethyl 2-bromoisobutyrate (0.627 ml, 0.0043 mol),powdered K₂CO₃ (0.773 g, 0.0056 mol), and MgSO₄ (0.168 g, 0.0014 mol).The reaction was stirred overnight at 77° C. Upon cooling, the reactionmixture was poured into 5N HCl and combined with EtOAc. The organiclayer was extracted with water followed by brine then concentrated todryness. Purification by flashed chromatography (1:1 hexanes:ethylacetate) gave the ester (0.135 g, 19%). C₂₈H₃₄F₂N₂O₄ (MW=500.25); massspectroscopy (MH⁺)=501.2

Step F

The ester from Step D (0.135 g, 0.00027 mol) was dissolved in methanol(4 ml) and treated with a solution of LiOH in water (1 ml). The reactionwas stirred overnight. The reaction was cooled and water (20 ml) wasadded to the solution. The solution was then acidified using 1N HCl topH=3 then extracted with ethyl acetate. The organic layer wasconcentrated to afford the desired carboxylic acid. C₂₆H₃₀F₂N₂O₄(MW=472.22); mass spectroscopy (MH⁺)=473.1

Step A

Following the procedure of Example 104, Step B, the product from Example103, Step A (11.0 g, 2.7 mmol), sodium hydride (Aldrich, 60% dispersionin mineral oil, 0.12 g, 3.0 mmol) and (bromomethyl)cyclopropane(Aldrich, 0.29 ml, 3.0 mmol) were used to yield the desired product(1.05 g). C₂₆H₃₂N₂O₃ (MW=420.6); MS (M+, 421.2)

Step B

Following the procedure of Example 103, Step C, the product from Example114, Step A (1.0 g, 2.4 mmol) and lithium aluminum hydride (Aldrich,0.14 g, 3.6 mmol) were used to yield the desired imidazolone as a crudeproduct (0.94 g). C₂₆H₃₂N₂O₂ (MW=404.6); MS (M+, 405.2)

Step C

Following the procedure of Example 104, Step D, the product from Example114, Step B (0.9 g, 2.2 mmol) and boron tribromide (Aldrich, 0.47 ml,5.0 mmol) were used to yield the crude product (0.9 g). C₂₅H₃₀N₂O₂(MW=390.5); MS (M+, 391.2, M-, 389.4)

Step D

Following the procedure of Example 103, Step E, the product from Example114, Step C (0.8 g, 2.0 mmol), ethyl 2-bromoisobutyrate (Aldrich, 0.9ml, 6.0 mmol), potassium carbonate (powdered, Aldrich, 1.1 g, 8.0 mmol)and magnesium sulfate (Mallinkrodt, 0.3 g, 2.5 mmol) were used to yieldthe product (0.7 g). C₃₁H₄₀N₂O₄ (MW=504.7); MS (M+, 505.4)

Step E

Following the procedure of Example 103, Step F, the product from Example114, Step D (0.7 g, 1.4 mmol), lithium hydroxide (0.07 g, 2.8 mmol),methanol (8 ml) and water (2 ml) were used to yield the desired productas a foam after evaporation of the solvent and placement under vacuum(0.295 g). C₂₉H₃₆N₂O₄ (MW=476.6); MS (M+, 477.3, M-, 475.2)

Example 115

Step A

A DMF solution (20 mL) of the hydantoin from Example 13 (960.6 mg, 3.87mmol) was treated sequentially with benzyl bromide (507 μL, 4.26 mmol),K₂CO₃ (1.2 g, 8.7 mmol), and MgSO₄ (1.2 g, 10.0 mmol). The resultingmixture was stirred at room temperature overnight. The reaction wasquenched by the slow addition of 1 N HCl (55 mL). The resulting mixturewas extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with brine then dried over Na₂SO₄ and concentrated.Purification by chromatography (gradient: 3:1 to 2:1 hexanes:ethylacetate) gave the desired alkylated hydantoin as a white solid (932.3mg, 71%). C₂₀H₂₂N₂O₃ (MW=338.41); mass spectroscopy: (MH⁺)=339.1,(MH⁻)=337.2

Step B

The hydantoin from Step A (897.8 mg, 2.65 mmol) was dissolved in DMF (15mL) and cooled to 0° C. under an atmosphere of N₂. The mixture wastreated with NaH (60% dispersion in oil, 125.5 mg, 3.0 mmol) and, after10 minutes, n-propyl iodide (297 μL, 3.0 mmol). The reaction mixture waswarmed to room temperature, stirred for 45 minutes, then quenched by theaddition of H₂O (0.5 mL). After stirring overnight, the mixture waspoured into 1 N HCl (50 mL). The resulting solution was extracted withethyl acetate (2×50 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated. Purification by chromatography (gradient: 5:1to 3:1 hexanes:ethyl acetate) gave the desired product as a yellowishoil (951.7 mg, 94%). C₂₃H₂₈N₂O₃ (MW=380.49); mass spectroscopy:(MH⁺)=381.1

Step C

The hydantoin from Step B (938.4 mg, 2.47 mmol) was dissolved in THF (20mL) and cooled to 0° C. under an atmosphere of N₂. LAH (145.7 mg, 3.8mmol) was added in one portion and, after 30 minutes, the reaction wasquenched by the addition of 5 N HCl (5 mL). The resulting mixture wasstirred at room temperature for 30 minutes then diluted with H₂O (150mL) and extracted with ethyl acetate (3×50 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄ and concentrated togive the desired imidazolone (871.3 mg, 97%). The crude product wascarried forward without further purification. C₂₃H₂₈N₂O₂ (MW=364.49);mass spectroscopy: (MH⁺)=365.3

Step D

The imidazolone from Step C (845.6 mg, 2.32 mmol) was dissolved inCH₂Cl₂ (20 mL) and cooled to 0° C. under an atmosphere of N₂. BBr₃ (1.0mL, 10.6 mmol) was added dropwise, then the reaction mixture was warmedto room temperature. After 30 min, the solution was again cooled to 0°C. and quenched by the slow addition of a methanol (1 mL) solution inCH₂Cl₂ (10 mL). Additional methanol:CH₂Cl₂ (1:1.10 mL) was added and thereaction was warmed to room temperature. The resulting mixture wasextracted with H₂O (50 mL). The aqueous extract was washed with CH₂Cl₂(50 mL) then the combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated to give the desired phenol as a foam(782.9 mg,96%). The crude product was carried forward without furtherpurification. C₂₂H₂₆N₂O₂ (MW=350.46); mass spectroscopy: (MH⁺)=351.3,(MH⁻)=349.0

Step E

An ethanol solution (20 mL) of the phenol from Step D (775 mg, 2.21mmol) was treated sequentially with ethyl 2-bromoisobutyrate (900 μL,6.6 mmol), K₂CO₃ (1.5 g, 10.9 mmol), and MgSO₄ (1.6 g, 13.3 mmol). Theresulting mixture was heated to 55-65° C. overnight. The reaction wasquenched by the slow addition of 1 N HCl (10 mL) then poured intoadditional 1 N HCl (50 mL). The resulting mixture was extracted withethyl acetate (2×50 mL). The combined organic extracts were washed withbrine then dried over Na₂SO₄ and concentrated. Purification bychromatography (gradient: 10:1 to 1:1 hexanes:ethyl acetate) gave thedesired ester as a slightly yellow oil (659.0 mg, 64%). C₂₈H₃₆N₂O₄(MW=464.61); mass spectroscopy: (MH⁺)=465.2

Step F

A dioxane solution (15 mL) of the ester from Step E (633.5 mg, 1.4 mmol)was treated with an aqueous solution (5 mL) of LiOH (100 mg, 4.2 mmol).The mixture was stirred at room temperature overnight. The solvent wasconcentrated and the resulting oil diluted with H₂O (50 mL) andextracted with Et₂O (50 mL). The aqueous extract was acidified with 1 NHCl and extracted with ethyl acetate (2×50 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, and concentrated togive the desired carboxylic acid as a slightly yellow foam-like solid(539.9 mg, 91%) C₂₆H₃₂N₂O₄ (MW 436.56); mass spectroscopy: (MH⁺)=437.3,(MH⁻)=435.1

Example 116

Step A

Following the procedure of Example 104, Step B, the product from Example16, Step A (0.5 g, 11.0 mmol), sodium hydride (Aldrich, 60% dispersionin mineral oil, 0.05 g, 1.1 mmol) and bromoethylmethyl ether (Aldrich,0.1 ml, 1.1 mmol) were used to yield the desired product (0.41 g).C₃₂H₄₄N₂O₆ (MW=552.7); ¹H NMR

Step B

Following the procedure of Example 25, Step B, the product from Example116, Step A (0.4 g, 0.72 mmol) and triflouroacetic acid (2 ml) were usedto yield the desired product (0.36 g). C₂₈H₃₆N₂O₆ (MW=496.6); MS (M+,497.3)

Step C

Following the procedure of Example 15, Step B, product from Example 116,Step B (0.36 g, 0.72 mmol) and sodium borohydride (0.54 g, 15.4 mmol)were used to yield the desired product after flash chromatography(methylene chloride:methanol) (0.032 g, 22%). C₂₈H₃₆N₂O₅ (MW=480.6); MS(M+, 481.1, M-, 479.0)

Example 117 Step A

Following the procedure of Example 104, Step B, the product from Example103, Step A (l.0 g, 2.7 mmol), sodium hydride (60% dispersion in mineraloil, 0.12 g, 3.0 mmol) and iodomethane (0.19 ml, 3.0 mmol) were used toyield the desired product (l.1 g). C₂₃H₂₈N₂O₃ (MW=380.5); MS (M+, 381.2)

Step B

Following the procedure of Example 103, Step C, the product from Example117, Step A (1.0 g, 2.7 mmol) and lithium aluminum hydride (0.16 g, 4.1mmol) were used to yield the desired imidazolone as a crude product(0.92 g). C₂₃H₂₈N₂O₂ (MW=364.5); MS (M+, 365.2)

Step C

Following the procedure of Example 104, Step D, the product from Example117, Step B (0.92 g, 2.5 mmol) and boron tribromide (0.47 ml, 5.0 mmol)were used to yield the crude product (0.86 g). C₂₂H₂₆N₂O₂ (MW=350.5); MS(M+, 351.2, M-, 349.3)

Step D

Following the procedure of Example 103, Step E, the product from Example117, Step C (0.85 g, 2.4 mmol), ethyl 2-bromoisobutyrate (1.1 ml, 7.2mmol), potassium carbonate (1.3 g, 9.6 mmol) and magnesium sulfate (0.4g, 3.0 mmol) were used to yield the product (0.75 g). C₂₈H₃₆N₂O₄(MW=464.6); MS (M+, 465.3)

Step E

Following the procedure of Example 103, Step F, the product from Example117, Step D (0.04 g, 0.04 mmol), sodium hydroxide (2N, 1 ml) andmethanol (4 ml) were used to yield the desired product after evaporationof the solvent and placement under vacuum (0.0095 g). C₂₆H₃₂N₂O₄(MW=436.6); MS (M+, 437.3, M-, 435.1)

Example 118

Step A

Following the procedure of Example 15, Step A, the hydantoin fromExample 13 (1.0 g, 4.0 mmol), 3-chlorobenzylbromide 0.67 ml, 4.4 mmol),potassium carbonate (2.2 g, 16.0 mmol) and magnesium sulfate (0.6 g, 5.0mmol) were used to yield the desired product (0.8 g). C₂₀H₂₁N₂O₃ cl(MW=372.9); MS (M+, 373.2)

Step B

Following the procedure of Example 104, Step B, the product from Example118, Step A (0.75 g, 2.0 mmol), sodium hydride (0.12 g, 3.0 mmol) andiodopropane (0.29 ml, 3.0 mmol) were used to yield the desired product(0.55 g). C₂₃H₂₇N₂O₃C1 (MW=414.9); MS (M+, 415.1)

Step C

Following the procedure of Example 103, Step C, the product from Example118, Step B (0.5 g, 1.2 mmol) and lithium aluminum hydride (0.07 g, 1.8mmol) were used to yield the desired imidazolone as a crude product (0.5g). C₂₃H₂₇N₂O₂C1 (MW=389.9); MS (M+, 390.2)

Step D

Following the procedure of Example 104, Step D, the product from Example118, Step C (0.5 g, 1.3 mmol) and boron tribromide (0.34 ml, 3.5 mmol)were used to yield the crude product (0.5 g). C₂₂H₂₅N₂O₂C1 (MW=384.9);MS (M+, 385.2)

Step E

Following the procedure of Example 103, Step E, the product from Example118, Step D (0.5 g, 1.3 mmol), ethyl 2-bromoisobutyrate (0.57 ml, 3.9mmol), potassium carbonate (0.7 g, 5.2 mmol) and magnesium sulfate (0.1g, 1.5 mmol) were used to yield the product (0.21 g). C₂₈H₃₅N₂O₄Cl(MW=499.1); MS (M+, 499.2)

Step F

Following the procedure of Example 103, Step F, the product from Example118, Step E (0.2 g, 0.4 mmol), sodium hydroxide (2N, 4 ml) and methanol(10 ml) were used to yield the desired product after evaporation of thesolvent and placement under vacuum (0.163 g). C₂₆H₃₁N₂O₄Cl (MW=471.0);¹H NMR

Example 119

Step A

The methoxy ether from Example 13 (1.0 g, 0.004 mol) was dissolved inDMF and treated with 3,4 difluoro bromobenzene (0.568 ml, 0.0044 mol)and powdered K₂CO₃ (2.20 g, 0.0080 mol). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was pouredinto 1N HCl and combined with ethyl acetate. The organic layer wasextracted and washed with brine then dried and concentrated.Purification of the crude material by flash chromatography (4:1hexanes:ethyl acetate; 1:1 hexanes:ethyl acetate) yielded the desiredhydantoin (0.530 g, 35%). C₂₀H₂₀F₂N₂O₃ (MW=374.14); mass spectroscopy(MH⁺)=375.2

Step B

The hydantoin from Step A (0.530 g, 0.00141 mol) was dissolved in DMF (5ml) and treated with NaH (0.062 g, 0.00156 mol) followed byl-iodo-propane (0.152 ml, 0.00156 mol). The reaction was stirredovernight under nitrogen. The reaction mixture was poured into 1N HCland combined with ethyl acetate. The organic layer was extracted andwashed with brine then dried and concentrated. Purification of the crudematerial by flash chromatography (2:1 hexanes:ethyl acetate) yielded thedesired product (0.505 g, 86%). C₂₃H₂₆F₂N₂O₃ (MW=416.19); massspectroscopy (MH⁺)-=417.2

Step C

Lithium aluminum hydride (0.0609 g, 0.0018 mol) was dissolved in THF (5ml). A THF solution of the hydantoin (0.505 g, 0.0012 mol) from Step Bwas added. The reaction was stirred overnight at room temperature. Thereaction was quenched by the addition of 5N HCl. After stirring forthirty minutes, water was added and the solution was extracted withethyl acetate. The organic layer was extracted and washed with brinethen dried and concentrated. The crude product was carried forth withoutfurther purification (0.483 g, 100%). C₂₃H₂₆F₂N₂O₂ (MW=400.20); massspectroscopy (MH⁺)=401

Step D

The methoxy ether from Step C (0.483 g, 0.0012 mol) was dissolved inmethylene chloride (5 ml) and cooled to 0° C. To this solution wasadded, dropwise, a solution of BBr₃ (0.228 ml, 0.0024 mol) in methylenechloride (5 ml). After stirring for about thirty minutes, the reactionmixture was cooled to 0° C. and quenched by the dropwise addition ofmethanol/methylene chloride. The solvent was concentrated and theresulting material was dissolved in methylene chloride. The organiclayer was extracted with water followed by brine. Upon evaporation ofthe solvent, the phenol (0.438 g, 95%) was obtained and was carriedforth without further purification. C₂₂H₂₄F₂N₂O₂ (MW=386.18); massspectroscopy (MH⁺)=387.2

Step E

The phenol from Step D (0.438 g, 0.00110 mol) was dissolved in EtOH (7ml) and treated with ethyl 2-bromoisobutyrate (0.500 ml, 0.0034 mol),powdered K₂CO₃ (0.607 g, 0.0044 mol), and MgSO₄ (0.132 g, 0.00110 mol).The reaction was stirred overnight at 77.7° C. Upon cooling, thereaction mixture was poured into 5N HCl and combined with EtOAc. Theorganic layer was extracted with water followed by brine thenconcentrated to dryness. Purification by flashed chromatography (1:1hexanes:ethyl acetate) gave the ester (0.267 g, 49%). C₂₈H₃₄F₂N₂O₄(MW=500.59); mass spectroscopy (MH⁺)=501.3

Step F

The ester from Step E (0.253 g, 0.00050 mol) was dissolved in methanol(4 ml) and treated with a solution of LiOH in water (1 ml). The reactionwas stirred overnight. The reaction was cooled and water (20 ml) wasadded to the solution. The solution was then acidified using 1N HCl topH=3 then extracted with ethyl acetate. The organic layer wasconcentrated to afford the desired carboxylic acid (0.112 g, 47%).C₂₆H₃₀F₂N₂O₄ (MW=472.22); mass spectroscopy (MH⁺)=473.2

Example 120

Step A

Following the procedure of Example 15, Step A, the hydantoin fromExample 13 (11.0 g, 4.0 mmol), 3,4-dichlorobenzylbromide (0.8 ml, 4.4mmol), potassium carbonate (2.2 g, 16.0 mmol) and magnesium sulfate (0.6g, 5.0 mmol) were used to yield the desired product (1.03 g).C₂₀H₂₀N₂O₃Cl₂ (MW=407.3); ¹H NMR

Step B

Following the procedure of Example 104, Step B, the product from Example120, Step A (11.0 g, 2.46 mmol), sodium hydride (0.11 g, 2.7 mmol) andiodopropane (0.26 ml, 2.71 mmol) were used to yield the desired product(0.91 g). C₂₃H₂₆N₂O₃Cl₂ (MW=449.4); MS (M+, 449.1, 451.1)

Step C

Following the procedure of Example 103, Step C, the product from Example120, Step B (0.9 g, 2.0 mmol) and lithium aluminum hydride (0.11 g, 3.0mmol) were used to yield the desired imidazolone as a crude product(0.85 g). C₂₃H₂₆N₂O₂Cl₂ (MW=433.4); MS (M+, 433.1, 435.1)

Step D

Following the procedure of Example 104, Step D, the product from Example120, Step C (0.85 g, 2.0 mmol) and boron tribromide (0.6 ml, 6.0 mmol)were used to yield the crude product. C₂₂H₂₄N₂O₂Cl₂ (MW=419.4); MS (M+,419.1, 421.1)

Step E

Following the procedure of Example 103, Step E, the product from Example120, Step D (0.8 g, 1.9 mmol), ethyl 2-bromoisobutyrate (0.83 ml, 5.7mmol), potassium carbonate (11.0 g, 7.6 mmol) and magnesium sulfate (0.3g, 2.5 mmol) were used to yield the product (0.48 g). C₂₈H₃₄N₂O₄Cl₂(MW=533.5); MS (M+, 533.2, 535.2)

Step F

Following the procedure of Example 103, Step F, the product from Example120, Step E (0.48 g, 0.9 mmol), lithium hydroxide (0.04 g, 1.8 mmol),methanol (8 ml) and water (2 ml) were used to yield the desired productafter evaporation of the solvent and placement under vacuum (0.45 g).C₂₆H₃₀N₂O₄Cl₂ (MW=505.5); MS (M+, 505.2, 507.2)

Example 121

Step A

Following the procedure of Example 15, Step A, the hydantoin fromExample 13 (1.0 g, 4.0 mmol), 4-fluorobenzylbromide (0.52 ml, 4.4 mmol),potassium carbonate (2.2 g, 16.0 mmol) and magnesium sulfate (0.6 g, 5.0mmol) were used to yield the desired product (1.0 g). C₂₀H₂₁N₂O₃F(MW=356.4); MS (M+, 357.2)

Step B

Following the procedure of Example 104, Step B, the product from Example121, Step A (1.0 g, 2.8 mmol), sodium hydride (0.12 g, 3.1 mmol) andiodopropane (0.3 ml, 3.1 mmol) were used to yield the desired product(0.85 g). C₂₃H₂₇N₂O₃F (MW=398.5); MS (M+, 399.2)

Step C

Following the procedure of Example 103, Step C, the product from Example121, Step B (0.85 g, 2.1 mmol) and lithium aluminum hydride (0.12 g, 3.2mmol) were used to yield the desired imidazolone as a crude product(0.64 g). C₂₃H₂₇N₂O₂F (MW=382.5); MS (M+, 383.2)

Step D

Following the procedure of Example 104, Step D, the product from Example121, Step C (0.64 g, 1.7 mmol) and boron tribromide (0.49 ml, 5.1 mmol)were used to yield the crude product. C₂₂H₂₅N₂O₂F (MW=368.5); MS (M+,369.2)

Step E

Following the procedure of Example 103, Step E, the product from Example121, Step D (0.62 g, 1.7 mmol), ethyl 2-bromoisobutyrate (0.74 ml, 5.1mmol), potassium carbonate (0.9 g, 6.8 mmol) and magnesium sulfate (0.3g, 2.5 mmol) were used to yield the product (0.49 g). C₂₈H₃₅N₂O₄F(MW=482.6); MS (M+, 483.3)

Step F

Following the procedure of Example 103, Step F, the product from Example121, Step-E (0.49 g, 11.0 mmol), sodium hydroxide (2N, 2 ml) andmethanol (8 ml) were used to yield the desired product after evaporationof the solvent and placement under vacuum (0.4 g). C₂₆H₃₁N₂O₄F(MW=454.6); MS (M+, 455.3, M-, 453.1)

Example 122

Step A

Following the procedure of Example 15, Step A, the hydantoin fromExample 13 (1.0 g, 4.0 mmol), 3,5-bistrifluoromethylbenzyl bromide (0.78ml, 4.4 mmol), potassium carbonate (2.2 g, 16.0 mmol) and magnesiumsulfate (0.6 g, 5.0 mmol) were used to yield the desired product (0.85g). C₂₂H₂₀N₂O₃F₆ (MW=474.4); MS (M+, 475.1)

Step B

Following the procedure of Example 104, Step B, the product from Example122, Step A (1.5 g, 3.2 mmol), sodium hydride (0.13 g, 3.5 mmol) andiodopropane (0.34 ml, 3.5 nmol) were used to yield the desired product(1.0 g). C₂₅H₂₆N₂O₃F₆ (MW=516.5); MS (M+, 517.2)

Step C

Following the procedure of Example 103, Step C, the product from Example122, Step B (1.0 g, 1.9 mmol) and lithium aluminum hydride (0.11 g, 2.9mmol) were used to yield the desired imidazolone as a crude product(0.84 g). C₂₅H₂₆N₂O₂F₆ (MW=500.5); MS (M+, 501.2)

Step D

Following the procedure of Example 104, Step D, the product from Example122, Step C (0.84 g, 1.7 mmol) and boron tribromide (0.49 ml, 5.1 mmol)were used to yield the crude product. C₂₄H₂₄N₂O₂F₆ (MW=486.5); MS (M+,487.2)

Step E

Following the procedure of Example 103, Step E, the product from Example122, Step D (0.62 g, 1.7 mmol), ethyl 2-bromoisobutyrate (0.74 ml, 5.1mmol), potassium carbonate (0.9 g, 6.8 mmol) and magnesium sulfate (0.3g, 2.5 mmol) were used to yield the product (0.57 g). C₃₀H₃₄N₂O₄F₆(MW=600.6); MS (M+, 601.3)

Step F

Following the procedure of Example 103, Step F, the product from Example122, Step E (0.57 g, 0.9 mmol), sodium hydroxide (2N, 2 ml) and methanol(8 ml) were used to yield the desired product after evaporation of thesolvent and placement under vacuum (0.54 g). C₂₈H₃₀N₂O₄F₆ (MW=572.6); MS(M+, 573.3, M-, 571.1)

Example 123

Step A

A DMF solution (50 mL) of the hydantoin from Example 13 (1.22 g, 4.2mmol) was treated sequentially with phenethyl bromide (574 μL, 4.2mmol), K₂CO₃ (1.3 g, 9.4 mmol), and MgSO₄ (1.8 g, 15 mmol). Theresulting mixture was stirred at room temperature overnight. Thereaction was quenched with 1 N HCl (200 mL) extracted with diethyl ether(1×200 mL). The organic extract was washed with brine then dried overNa₂SO₄ and concentrated. Purification by chromatography (gradient: 2:1to 1:1 hexanes:ethyl acetate) gave the desired alkylated hydantoin as awhite solid (766.6 mg, 52%). C₂₁H₂₄N₂O₃ (MW=352.44); mass spectroscopy:(MH⁺)=353.2, (MH⁻)=351.3

Step B

The hydantoin from Step A (761.5 mg, 2.16 mmol) was dissolved in DMF (15mL) and cooled to 0° C. under an atmosphere of N₂. The mixture wastreated with NaH (60% dispersion in oil, 101 mg, 2.52 mmol) and, after15 minutes, n-propyl iodide (243 μL, 2.49 mmol). The reaction mixturewas warmed to room temperature, stirred overnight, then poured into 1 NHCl (100 mL). The resulting solution was extracted with diethyl etherand the organic extract was dried over Na₂SO₄ and concentrated.Purification by chromatography (gradient: 5:1 to 3:1 hexanes:ethylacetate) gave the desired product as a colorless oil (720.8 mg, 85%).C₂₄H₃₀N₂O₃ (MW=394.52); mass spectroscopy: (MH⁺)=395.3

Step C

The hydantoin from Step B (704.9 mg, 1.79 mmol) was dissolved in THF (20mL) and cooled to 0° C. LAH (68 mg, 1.79 mmol) was added in one portionand, after 45 minutes, the reaction was quenched by the addition of 5 NHCl (5 mL). The resulting mixture was stirred at room temperature for 30minutes then diluted with H₂O (100 mL) and extracted with ethyl acetate(2×50 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄ and concentrated to give the desired imidazolone (667.6 mg,99%). The crude product was carried forward without furtherpurification. C₂₄H₃₀N₂O₂ (MW=378.52); mass spectroscopy: (MH⁺)=379.2

Step D

The imidazolone from Step C (659.4 mg, 1.74 nmol) was dissolved inCH₂Cl₂ (20 mL) and cooled to 0° C. BBr₃ (823 μL, 8.70 mmol) was addeddropwise, then the reaction mixture was warmed to room temperature.After 1 hour, the solution was again cooled to 0° C. and quenched by theslow addition of a methanol:CH₂Cl₂ (1:4) solution. The resulting mixturewas extracted with H₂O (50 mL). The aqueous extract was washed withCH₂Cl₂ (50 mL) then the combined organic extracts were washed withbrine, dried over Na₂SO₄, and concentrated to give the desired phenol asa foam. The crude product was carried forward without furtherpurification. C₂₃H₂₈N₂O₂ (MW=364.49); mass spectroscopy: (MH⁺)=365.3,(MH⁻)=363.3

Step E

A DMF solution (20 mL) of the phenol from Step D was treatedsequentially with ethyl 2-bromoisobutyrate (725 μL, 5.35 mmol), K₂CO₃(1.2 g, 8.7 mmol), and MgSO₄ (1.2 g, 10 mmol). The resulting mixture washeated to 55-65° C. for two days. The reaction was quenched with 1 N HCl(100 mL) then extracted with diethyl ether (2×70 mL). The combinedorganic extracts were washed with brine then dried over Na₂SO₄ andconcentrated. Purification by chromatography (gradient: 2:1 to 1:1hexanes:ethyl acetate) gave the desired ester as a slightly yellow oil(325.6 mg, 39% for two steps). C₂₉H₃₈N₂O₄ (MW=478.64); massspectroscopy: (MH⁺)=479.4

Step F

A dioxane solution (10 mL) of the ester from Step E (317.6 mg, 0.66mmol) was treated with an aqueous solution (5 mL) of LiOH (53 mg, 2.2mmol). The mixture was stirred at room temperature for two hours. Thesolvent was concentrated and the resulting oil diluted with H₂O (50 mL)and 1 N NaOH (10 mL), then extracted with Et₂O (50 mL). The aqueousextract was acidified with 1 N HCl and extracted with diethyl ether(2×50 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated to give the desired carboxylic acid as afoam-like solid (253.6 mg, 85%) C₂₇H₃₄N₂O₄ (MW=450.58); massspectroscopy: (MH⁺)=451.3, (MH⁻)=449.1

Step A

A DMF solution (50 mL) of the hydantoin from Example 13 (1.02 g, 4.1mmol) was treated with a DMF solution (10 mL) 4-isopropylbenzyl bromide(0.693 g, 4.1 mmol) followed by K₂CO₃ (1.2 g, 8.7 mmol), and MgSO₄ (1.2g, 10 mmol). The resulting mixture was stirred at room temperatureovernight. The reaction was poured into 1 N HCl (150 mL) then extractedwith ethyl acetate (2×100 mL). The combined organic extracts were washedwith brine then dried over Na₂SO₄ and concentrated. Purification bychromatography (gradient: 3:1 to 1:1 hexanes:ethyl acetate) gave thedesired alkylated hydantoin as a white solid (842.5 mg, 54%). C₂₃H₂₈N₂O₃(MW=380.49); mass spectroscopy: (MH⁺)=381.3, (MH⁻)=379.1

Step B

The hydantoin from Step A (827.3 mg, 2.17 mmol) was dissolved in DMF (15mL) and cooled to 0° C. The mixture was treated with NaH (60% dispersionin oil, 106 mg, 2.65 mmol) and, after 15 minutes, n-propyl iodide (244μL, 2.50 mmol). The reaction mixture was warmed to room temperature,stirred overnight, then poured into 1 N HCl (100 mL). The resultingsolution was extracted with diethyl ether and the organic extract waswashed with brine, dried over Na₂SO₄ and concentrated. Purification bychromatography (gradient: 5:1 to 3:1 hexanes:ethyl acetate) gave thedesired product as a colorless oil (705.3 mg, 77%). C₂₆H₃₄N₂O₃(MW=422.57); mass spectroscopy: (MH⁺)=423.3

Step C

The hydantoin from Step B (687.0 mg, 1.63 mmol) was dissolved in THF (20mL) and cooled to 0° C. LAH (63 mg, 1.66 mmol) was added in one portionand, after 45 minutes, the reaction was quenched by the addition of 5 NHCl (5 mL) in THF (10 ml). The resulting mixture was stirred at roomtemperature for 30 minutes then diluted with H₂O (100 mL) and extractedwith ethyl acetate (2×50 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄ and concentrated to give the desiredimidazolone (640.1 mg, 97%). The crude product was carried forwardwithout further purification. C₂₆H₃₄N₂O₂ (MW=406.57); mass spectroscopy:(MH⁺)=407.2

Step D

The imidazolone from Step C (630.8 mg, 1.55 mmol) was dissolved inCH₂Cl₂ (20 mL) and cooled to 0° C. BBr₃ (733 μL, 7.75 mmol) was addeddropwise, then the reaction mixture was warmed to room temperature.After 1 hour, the solution was again cooled to 0° C. and quenched by theslow addition of a methanol:CH₂Cl₂ (1:4) solution. The resulting mixturewas extracted with H₂O (50 mL). The aqueous extract was washed withCH₂Cl₂ (50 mL) then the combined organic extracts were washed withbrine, dried over Na₂SO₄, and concentrated to give the desired phenol asa foam. The crude product was carried forward without furtherpurification. C₂₅H₃₂N₂O₂ (MW 392.55); mass spectroscopy: (MH⁺)=393.3,(MH⁻)=391.4

Step E

A DMF solution (20 mL) of the phenol from Step D was treatedsequentially with ethyl 2-bromoisobutyrate (650 μL, 4.8 mmol), K₂CO₃(1.1 g, 8.0 mmol), and MgSO₄ (1.1 g, 9.2 mmol). The resulting mixturewas heated to 55-65° C. for two days. The reaction was quenched with 1 NHCl (100 mL) then extracted with diethyl ether (2×75 mL). The combinedorganic extracts were washed with brine then dried over Na₂SO₄ andconcentrated. Purification by chromatography (gradient: 2:1 to 1:1hexanes:ethyl acetate) gave the desired ester as a slightly yellow oil(202.1 mg, 26% for two steps). C₂₇H₄₂N₂O₄ (MW=506.69); massspectroscopy: (MH⁺)=507.4

Step F

A dioxane solution (10 mL) of the ester from Step E (194.5 mg, 0.43mmol) was treated with an aqueous solution (5 mL) of LiOH (45 mg, 1.9mmol). The mixture was stirred at room temperature for two hours. Thesolvent was concentrated and the resulting oil diluted with H₂O (50 mL)and 1 N NaOH (10 mL), then extracted with Et₂O (50 mL). The aqueousextract was acidified with 1 N HCl and extracted with diethyl ether(2×50 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, and concentrated to give the desired carboxylic acid as afoam-like solid (163.0 mg, 79%) C₂₉H₃₈N₂O₄ (MW=478.64); massspectroscopy: (MH⁺)=479.3, (MH⁻)=477.1

Example 125

Step A

Following the procedure of Example 15, Step A, the hydantoin fromExample 13 (1.0 g, 4.0 mmol), 4-ethylbenzyl chloride (0.7 ml, 4.4 mmol),potassium carbonate (2.2 g, 16.0 mmol) and magnesium sulfate (0.6 g, 5.0mmol) were used to yield the desired product (0.9 g). C₂₂H₂₆N₂O₃(MW=366.5°); MS (M-, 365.1)

Step B

Following the procedure of Example 104, Step B, the product from Example125, Step A (0.9 g, 2.5 mmol), sodium hydride (0.12 g, 2.8 mmol) andiodopropane (0.3 ml, 2.8 mmol) were used to yield the desired product(0.77 g). C₂₅H₃₂N₂O₃ (MW=408.6); MS (M+, 409.3)

Step C

Following the procedure of Example 103, Step C, the product from Example125, Step B (0.76 g, 1.9 mmol) and lithium aluminum hydride (0.11 g, 2.9mmol) were used to yield the desired imidazolone as a crude product(0.72 g). C₂₅H₃₂N₂O₂ (MW=392.6); MS (M+, 393.3)

Step D

Following the procedure of Example 104, Step D, the product from Example125, Step C (0.72 g, 1.8 mmol) and boron tribromide (Aldrich, 0.52 ml,5.4 mmol) were used to yield the crude product. C₂₄H₃₀N₂O₂ (MW=378.5);MS (M+, 379.2)

Step E

Following the procedure of Example 103, Step E, the product from Example125, Step D (0.68 g, 1.8 mmol), ethyl 2-bromoisobutyrate (0.83 ml, 5.4mmol), potassium carbonate (11.0 g, 7.2 mmol) and magnesium sulfate(0.36 g, 3.0 mmol) were used to yield the product (0.29 g). C₃₀H₄₀N₂O₄(MW=492.7); MS (M+, 493.3)

Step F

Following the procedure of Example 103, Step F, the product from Example125, Step E (0.49 g, 11.0 mmol), sodium hydroxide (2N, 1 ml) andmethanol (4 ml) were used to yield the desired product after evaporationof the solvent and placement under vacuum. C₂₈H₃₆N₂O₄ (MW=464.6); MS(M+, 465.2, M-, 463.4)

Step A

The product from Example 16, Step A (0.6 g, 1.2 mmol) and 4-picolylchloride hydrochloride (0.2 ml, 1.3 mmol) and triethylamine (0.2 ml)stirred together in DMF (20 ml). Potassium carbonate (0.7 g, 4.8 mmol)and magnesium sulfate (0.2 g, 1.5 mmol) added and the mixture stirred atambient temperature overnight. The reaction mixture was carefully addedto 1 N hydrochloric acid (50 ml) and the resulting solution wasextracted twice with ethyl acetate. The organic layers were combined,washed with aqueous brine then dried over sodium sulfate. Evaporation ofthe solvent and subsequent purification by flash chromatography(hexanes:ethyl acetate) gave the desired product (0.42 g). C₃₅H₄₃N₃O₅(MW=585.8); MS (M+, 586.3)

Step B

Following the procedure of Example 25, Step B, the product from Example126, Step A (0.4 g, 0.7 mmol) and triflouroacetic acid (2 ml) were usedto yield the desired product. C₃₁H₃₅N₃O₅ (MW=529.6); MS (M+, 530.4)

Following the procedure of Example 15, Step B, product from Example 126,Step B (0.35 g, 0.7 mmol) and sodium borohydride (0.28 g, 7.5 mmol) wereused to yield the desired product after flash chromatography (methylenechloride:methanol). C₃₁H₃₅N₃O₄ (MW=513.6); MS (M+, 514.4, M-, 512.2)

Step C

Step A

Following the procedure of Example 15, Step A, the hydantoin fromExample 13 (1.0 g, 4.0 mmol), iodopropane (0.43 ml, 4.4 mmol), potassiumcarbonate (2.2 g, 16.0 mmol) and magnesium sulfate (0.6 g, 5.0 mmol)were used to yield the desired product (0.95 g). C₁₆H₂₂N₂O₃ (MW=290.4);MS (M+, 291.2)

Step B

Following the procedure of Example 104, Step B, the product from Example127, Step A (0.9 g, 3.1 mmol), sodium hydride (0.13 g, 3.4 mmol) and3,4-dimethylbenzyl chloride (0.5 ml, 3.4 mmol) were used to yield thedesired product (1.1 g). C₂₅H₃₂N₂O₃ (MW=408.6); MS (M+, 409.3)

Step C

Following the procedure of Example 103, Step C, the product from Example127, Step B (0.8 g, 1.9 mmol) and lithium aluminum hydride (0.16 g, 4.1mmol) were used to yield the desired imidazolone as a crude product (0.8g) C₂₅H₃₂N₂O₂ (MW=392.6); MS (M+, 393.3)

Step D

Following the procedure of Example 104, Step D, the product from Example127, Step C (0.8 g, 2.1 mmol) and boron tribromide (0.6 ml, 6.3 mmol)were used to yield the crude product (0.7 g). C₂₄H₃₀N₂O₂ (MW=378.5); MS(M+, 379.2)

Step E

Following the procedure of Example 103, Step E, the product from Example127, Step D (0.7 g, 1.8 mmol), ethyl 2-bromoisobutyrate (0.8 ml, 5.4mmol), potassium carbonate (11.0 g, 7.2 mmol) and magnesium sulfate (0.4g, 3.0 mmol) were used to yield the product (0.42 g). C₃₀H₄₀N₂O₄(MW=492.7); MS (M+, 493.3)

Step F

Following the procedure of Example 103, Step F, the product from Example127, Step E (0.4 g, 11.0 mmol), sodium hydroxide (2N, 1.5 ml) andmethanol (5 ml) were used to yield the desired product after evaporationof the solvent and placement under vacuum. C₂₈H₃₆N₂O₄ (MW=464.6); MS(M+, 465.3, M-, 463.1)

A CH₂Cl₂ solution (15 mL) of the ester from Example 16, Step A (279.9mg, 0.57 mmol) was cooled to 0° C. and treated with TFA (1 mL, 13 mmol).The mixture was warmed to room temperature and stirred for 1.5 hours.The solvent was concentrated to give the crude acid, which was dissolvedin 1 N NaOH (25 mL) and washed with diethyl ether (25 mL). The acueoussolution was then acidified with 5 N HCl and extracted with diethylether (1×25 mL) and ethyl acetate (1×25 mL). The combined organicextracts were dried over Na₂SO₄ and concentrated to give the desiredcaboxylic acid as a white foam (257.3 mg). C₂₅H₃N₂O₅ (MW=438.53); massspectroscopy: (MH⁺)=439.1,

see Example 22, Step B

Step A

The hydantoin from Example 16, Step A (234.0 mg, 0.47 mmol) wasdissolved in DMF (20 mL) and cooled to 0° C. under an atmosphere of N₂.The mixturefwas treated with NaH (60% dispersion in oil, 25 mg, 0.63mmol) and, after 10 minutes, n-propyl iodide (55 μL, 0.56 mmol). Thereaction mixture was warmed to room temperature, stirred overnight, thenpoured into 1 N HCl (100 mL). The resulting solution was extracted withdiethyl ether (2×70 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated. Purification by chromatography (5:1hexanes:ethyl acetate) gave the desired product as a colorless oil (70.8mg, 28%). C₃₂H₄₄N₂O₅ (MW=536.72); mass spectroscopy:(MH+-t-butyl)=481.4, (M+NH₄+)=554.5

Step B

A CH₂Cl₂ solution (10 mL) of the ester from Step A (65 mg, 0.12 mmol)was cooled to 0° C. and treated with TFA (0.5 mL, 6.5 mmol). The mixturewas warmed to room temperature and stirred for 2 hours. The solvent wasconcentrated to give the crude acid, which was dissolved in 1 N NaOH (50mL) and washed with diethyl ether (50 mL). The aqueous solution was thenacidified with 5 N HCl and extracted with ethyl acetate (2×25 mL). Thecombined organic extracts were dried over Na₂SO₄ and concentrated togive the desired caboxylic acid as a colorless oil (55.1 mg, 95%).C₂₈H₃₆N₂O₅ (MW=480.61); mass spectroscopy: (MH⁺)=481.2, (MH⁻)=479.3

Step A

The hydantoin from Example 22, Step A (1.06 g, 2.05 mmol) was dissolvedin DMF (25 mL) and cooled to 0° C. under an atmosphere of N₂. Themixture was treated with NaH (60% dispersion in oil, 101 mg, 2.5 mmol)and, after 5 minutes, a slight excess of 4-methoxybenzyl chloride. Thereaction mixture was warmed to room temperature, stirred for 2 hours,then poured into 1 N HCl (100 mL). The resulting solution was extractedwith diethyl ether (2×100 mL). The combined organic extracts were washedwith brine, dried over Na₂SO₄ and concentrated. Purification bychromatography (2:1 hexanes:ethyl acetate) gave the desired product as acolorless oil (70.8 mg, 28%). C₃₉H₄₄N₂O₆ (MW=636.80); mass spectroscopy:(M+NH₄+)=654.4

Step B

A CH₂Cl₂ solution (10 mL) of the ester from Step A (55 mg, 0.086 mmol)was cooled to 0° C. and treated with TFA (0.5 mL, 6.5 mmol). The mixturewas warmed to room temperature and stirred for 2 hours. The solvent wasconcentrated to give the crude acid, which was dissolved in 1 N NaOH (50mL) and washed with diethyl ether (50 mL). The aqueous solution was thenacidified with 5 N HCl and extracted with ethyl acetate (50 mL). Theorganic extract was dried over Na₂SO₄ and concentrated to give thedesired caboxylic acid (55.4 mg). C₃₅H₃₆N₂O₆ (MW=580.69); massspectroscopy: (MH⁺)=581.2, (MH⁻)=579.4

Step A

The 4-(4-methoxyphenyl) butyric acid (10.04 g, 0.052 mol) andhydroxylamine (5.04 g, 0.052 mol) were combined in THF and treated withEDAC (11.86 g, 0.062 mol), HOBt (7.0 g, 0.052 mol) and diisopropyl ethylamine (16.9 ml, 0.124 mol). The reaction was stirred overnight. Thereaction was concentrated to one-half its original volume. Ethyl acetate(100 ml) was added and the solution was extracted with 1N HCl. Theorganic layer was washed with 2N NaOH then concentrated. Purification ofthe crude material by flash chromatography (2:1 hexanes:ethyl acetate)gave the Weinreb amide (9.77 g, 78%). C₁₃H₁₉NO₃ (MW=237.14); massspectroscopy (MH⁺)=238.0

Step B

The Weinreb amide from Step A (4.7 g, 0.0198 mol) was dissolved in ether(164 ml) and cooled to 0° C. Methyl magnesium bromide (3.0 M in ether,33 ml, 99 mmol) was added slowly to the reaction mixture. The reactionwas stirred overnight. Hydrochloric acid (1N, 50 ml) was and the mixturewas extracted with ether. The organic layer was stripped to afford themethyl ketone as a clear oil (3.66 g, 96%). C₁₂H₁₆O₂ (MW=192.12); massspectroscopy (MH⁺)=192.1

Step C

The methyl ketone from Step B (3.66 g, 0.0190 mol) was combined withpotassium cyanide (2.73 g, 0.042 mol) and ammonium carbonate (9.13 g,0.095 mol) in 1:1 methanol: water (35:35 ml) and stirred overnight at50° C. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine thenconcentrated. Purification of the crude material by flash chromatograhy(2:1 hexanes:ethyl acetate) yielded the desired hydantoin as a thick,clear oil. C₁₄H₁₈N₂O₃ (MW=262.13); mass spectroscopy (MH⁺)=263.1

Step D

The hydantoin from Step C (1 g, 0.0038 mol) was dissolved in DMF (20 ml)and treated with K₂CO₃ (2.09 g, 0.0152 mol) and magnesium sulfate (0.689g, 0.0057 mol) followed by 3, 5 difluoro-bromobenzene (0.543 ml, 0.0042mol). The reaction was stirred overnight. Hydrochloric acid was addedand the mixture was extracted with ethyl acetate. The organic layer wasconcentrated. Purification of the crude material by flash chromatography(4:1 ethyl acetate:hexanes) give the alkylated hydantoin (1.12 g, 76%).C₂₁H₂₂F₂N₂O₃ (MW=388.16); mass spectroscopy (MH⁺)=389.2

Step E

Sodium hydride (0.121 g, 0.0030 mol) was suspended in DMF (5 ml) andcooled to OoC. The hydantoin from Step D (1.07 g, 0.00276 mol) was addedas a solution in DMF (5 ml). Iodopropane (0.295 ml, 0.0030 mol) wassyringed into solution and the reaction was stirred overnight at roomtemperature. The reaction mixture was poured into 1N HCl and extractedwith ethyl acetate. Purification of the crude material by flashchromatography (4:1 hexanes:ethyl acetate) gave the desired product as aclear oil (0.951 g, 80%). C₂₄H₂₈F₂N₂O₃ (MW=430.21); mass spectroscopy(MH⁺)=431.2

Step F

The methoxy ether from Step E (0.951 g, 0.0022 mol) was dissolved inmethylene chloride (5 ml) and cooled to 0° C. To this solution wasadded, dropwise, a solution of BBr₃ (0.418 ml, 0.0044 mol) in methylenechloride (5 ml). After stirring for about twenty minutes, the reactionmixture was cooled to 0° C. and quenched by the dropwise addition ofmethanol/methylene chloride. The solvent was concentrated and theresulting material was dissolved in methylene chloride. The organiclayer was extracted with water followed by brine. Upon evaporation ofthe solvent, the phenol (0.910 g, 99%) was obtained and was carriedforth without further purification. C₂₃H₂₆F₂N₂O₃ (MW=416.19); massspectroscopy (MH⁺)=417.2

Step G

The phenol from Step F (0.910 g, 0.00220 mol) was dissolved in EtOH andtreated with ethyl 2-bromoisobutyrate (0.963 ml, 0.0066 mol), powderedK₂CO₃ (1.210 g, 0.0088 mol), and MgSO₄ (0.264 g, 0.0022 mol). Thereaction was stirred overnight at 77.7° C. Upon cooling, the reactionmixture was poured into 5N HCl and combined with EtOAc. The organiclayer was extracted with water followed by brine then concentrated todryness. Purification by flashed chromatography (5:1 hexanes:ethylacetate) gave the ester (0.850 g, 69%). C₂₉H₃₆F₂N₂O₅ (MW=530.26); massspectroscopy (MH⁺)=531.3

Step H

The ester from Step G (0.500 g, 0.00094 mol) was dissolved in methanol(8 ml) and treated with a solution of LiOH in water (2 ml). The reactionwas stirred overnight. The reaction was cooled and water was added tothe solution. The solution was then acidified using 1N HCl to pH=3 thenextracted with ethyl acetate. The organic layer was concentrated toafford the desired carboxylic acid (0.112 g, 47%). Purification of thecrude material using reverse phase chromatography (7:3 acetonitrile:water) afforded the desired acid (0.033 mg, 7%) C₂₇H₃₂F₂N₂O₅(MW=502.23); mass spectroscopy (MH⁺)=503.3

Step A

The 4-(4-methoxyphenyl) butyric acid (10.04 g, 0.052 mol) andhydroxylamine (5.04 g, 0.052 mol) were combined in THF and treated withEDAC (11.86 g, 0.062 mol), HOBt (7.0 g, 0.052 mol) and diisopropyl ethylamine (16.9 ml, 0.124 mol). The reaction was stirred overnight. Thereaction was concentrated to one-half its original volume. Ethyl acetate(100 ml) was added and the solution was extracted with 1N HCl. Theorganic layer was washed with 2N NaOH then concentrated. Purification ofthe crude material by flash chromatography (2:1 hexanes:ethyl acetate)gave the Weinreb amide (9.77 g, 78%). C₁₃H₁₉NO₃ (MW=237.14); massspectroscopy (MH⁺)=238.0

Step B

The Weinreb amide from Step A (4.7 g, 0.0198 mol) was dissolved in ether(164 ml) and cooled to 0° C. Methyl magnesium bromide (3.0 M in ether,33 ml, 99 mmol) was added slowly to the reaction mixture. The reactionwas stirred overnight. Hydrochloric acid (1N, 50 ml) was and the mixturewas extracted with ether. The organic layer was stripped to afford themethyl ketone as a clear oil (3.66 g, 96%). C₁₂H₁₆O₂ (MW=192.12); massspectroscopy (MH⁺)=192.1

Step C

The methyl ketone from Step B (3.66 g, 0.0190 mol) was combined withpotassium cyanide (2.73 g, 0.042 mol) and ammonium carbonate (9.13 g,0.095 mol) in 1:1 methanol: water (35:35 ml) and stirred overnight at50° C. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine thenconcentrated. Purification of the crude material by flash chromatograhy(2:1 hexanes:ethyl acetate) yielded the desired hydantoin as a thick,clear oil. C₁₄H₁₈N₂O₃ (MW=262.13); mass spectroscopy (MH⁺)=263.1

Step D

The hydantoin from Step C (1 g, 0.0038 mol) was dissolved in DMF (20 ml)and treated with K₂CO₃ (2.09 g, 0.0152 mol) and magnesium sulfate(0.68.9 g, 0.0057 mol) followed by 3, 4 dimethyl-chlorobenzene (0.607ml, 0.0042 mol). The reaction was stirred overnight. Hydrochloric acidwas added and the mixture was extracted with ethyl acetate. The organiclayer was concentrated. Purification of the crude material by flashchromatography (2:1 ethyl acetate:hexanes) gave the alkylated hydantoin(1.30 g, 91%). C₂₃H₂₈N₂O₃ (MW=380.21); mass spectroscopy (MH⁺)=381.2

Step E

Sodium hydride (0.150 g, 0.0038 mol) was suspended in DMF (5 ml) andcooled to 0° C. The hydantoin from Step D (1.30 g, 0.00340 mol) wasadded as a solution in DMF (5 ml). Iodopropane (0.367 ml, 0.0038 mol)was syringed into solution and the reaction was stirred overnight atroom temperature. The reaction mixture was poured into 1N HCl andextracted with ethyl acetate. Purification of the crude material byflash chromatography (2:1 hexanes:ethyl acetate) gave the desiredproduct as a clear oil (1.27 g, 89%). C₂₆H₃₄N₂O₃ (MW=422.26); massspectroscopy (MH⁺)=423.2

Step F

The methoxy ether from Step E (1.27 g, 0.0030 mol) was dissolved inmethylene chloride (10 ml) and cooled to 0° C. To this solution wasadded, dropwise, a solution of BBr₃ (0.569 ml, 0.0060 mol) in methylenechloride (5 ml). After stirring for about twenty minutes, the reactionmixture was cooled to 0° C. and quenched by the dropwise addition ofmethanol/methylene chloride. The solvent was concentrated and theresulting material was dissolved in methylene chloride. The organiclayer was extracted with water followed by brine. Upon evaporation ofthe solvent, the phenol (1.19 g, 98%) was obtained and was carried forthwithout further purification. C₂₅H₃₂N₂O (MW=408.24); mass spectroscopy(MH⁺) 409.2

Step G

The phenol from Step F (1.19 g, 0.00290 mol) was dissolved in EtOH andtreated with ethyl 2-bromoisobutyrate (1.28 ml, 0.0087 mol), powderedK₂CO₃ (1.610 g, 0.0117 mol), and MgSO₄ (0.348 g, 0.0029 mol). Thereaction was stirred overnight at 77.7° C. Upon cooling, the reactionmixture was poured into 5N HCl and combined with EtOAc. The organiclayer was extracted with water followed by brine then concentrated todryness. Purification by flashed chromatography (5:1 hexanes:ethylacetate) gave the ester (1.26 g, 83%). C₃₁H₄₂N₂O₃ (MW=522.31); massspectroscopy (MH⁺)=

Step H

The ester from Step G (0.500 g, 0.00095 mol) was dissolved in methanol(8 ml) and treated with a solution of LiOH in water (2 ml). The reactionwas stirred overnight. The reaction was cooled and water was added tothe solution. The solution was then acidified using 1N HCl to pH=3 thenextracted with ethyl acetate. The organic layer was concentrated toafford the desired carboxylic acid (0.239 g, 51%). Purification of thecrude material using reverse phase chromatography (7:3 acetonitrile:water) afforded the desired acid (0.033 mg, 7%). C₂₉H₃₈N₂O₅ (MW=494.28);mass spectroscopy (ME+)=495.3

Step A

The diester from Example 14, Step B (10 g, 0.032 mol) was dissolved indioxane. A solution of LiOH in water was added, dropwise, over a periodof ten minutes. The reaction was allowed to stir for two hours. Thesolvent was concentrated and the resulting residue was redisssolved inwater then washed with ether. The aqueous solution was acidified with 5NHCl and extracted with ethyl acetate (2×). The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered, and concentrated toafford the desired acid as an yellow oil (9.61 g, 93%). C₁₈H₂₆O₅(MW=322.18); mass spectroscopy (MH⁺)=321.0

Step B

The acid from Step A (9.60 g, 0.0298 mol) was combined with N-methyl,O-methyl hydroxylamine, EDAC (6.83 g, 0.0358 mol), HOBt (4.02 g, 0.0298mol), and DIEA (10 ml, 0.075 mol) in THF (80 ml). The reaction wasallowed to stir overnight at room temperature. The solvent wasconcentrated and the resulting material was redissolved in ethyl acetateand extracted with 1N HCl followed by brine. The organic layer wasconcentrated. Purification by flash chromatography (4:1 hexane:ethylacetate) gave the Weinreb amide (7.23 g, 66%). C₂₆H₃₁NO₅ (MW=365.22);mass spectroscopy (MH⁺)=366.22

Step C

A THF solution (50 ml) of the Weinreb amide from Step B (3.4 g, 0.0093mol) was cooled to −78° C. and methyl magnesium bromide (3.0 M in ether,15 ml, 0.046 mol) was added to the solution. After stirring for twohours, 1N HCl was added to quench the reaction. The reaction mixture wasextracted with ether. The ethereal layer was concentrated. Purificationby flash chromatography (9:1 hexanes:ethyl acetate) yielded the methylketone as a colorless oil (1.77 g, 60%). C₁₉H₂₈O₄ (MW=320.20); massspectroscopy (MH⁺)=321.0

Step D

The methyl ketone from Step C (1.77 g, 0.0055 mol) was combined withpotassium cyanide (0.792 g, 0.0122 mol) and ammonium carbonate (2.65 g,0.0277 mol) in 1:1 methanol: water (20:20 ml) and stirred overnight at50° C. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine then concentratedto afford the hydantoin as a white solid (2.11 g, 99%) which was carriedforth without further purification. C₂₃H₃₀N₂O₅ (MW=390.22); massspectroscopy (MH⁺)=391.3

Step E

The hydantoin from Step D (0.600 g, 0.0015 mol) was dissolved in DMF (10ml) and treated with K₂CO₃ (0.849 g, 0.0060 mol) and magnesium sulfate(0.271 g, 0.0023 mol) followed by 3, 4 dimethyl benzyl chloride (0.245ml, 0.00169 mol). The reaction was stirred overnight at 45° C.Hydrochloric acid (5N) was added and the mixture was extracted withethyl acetate (2×). The organic layer was concentrated. Purification ofthe crude material by flash chromatography (4:1 ethyl acetate:hexanes;2:1 ethyl acetate:hexanes) give the alkylated hydantoin (0.560 g, 73%).C₃₀H₄₀N₂O₅ (MW=508.29); mass spectroscopy (MH⁺) 509.4

Step F

The ester from Step E (0.560 g, 0.0011 mol) was dissolved indichloromethane (10 ml) and treated with trifluoroacetic acid (0.425ml). The reaction was stirred overnight. The solution was concentratedand the resulting residue was redissolved in water and extracted withmethylene chloride. The organic layer was extracted with 2N NaOH. Whileallowing the layers to separate, a white precipitate crashed out ofsolution. The solid was filtered; spectral data indicated that the solidwas the desired carboxylic acid (0.170 g, 34%). C₂₆H₃₂N₂O₅ (MW=452.23);mass spectroscopy (MH⁺)=453.3

Step A

The diester from Example 14, Step B (10 g, 0.032 mol) was dissolved indioxane. A solution of LiOH in water was added, dropwise, over a periodof ten minutes. The reaction was allowed to stir for two hours. Thesolvent was concentrated and the resulting residue was redisssolved inwater then washed with ether. The aqueous solution was acidified with 5NHCl and extracted with ethyl acetate (2×).

The combined organic layers were washed with brine, dried over Na₂SO₄,filtered, and concentrated to afford the desired acid as a yellow oil(9.61 g, 93%). C₁₈H₂₆O₅ (MW=322.18); mass spectroscopy (MH−)=321.0

Step B

The acid from Step A (9.60 g, 0.0298 mol) was combined with N-methyl,O-methyl hydroxylamine, EDAC (6.83 g, 0.0358 mol), HOBt (4.02 g, 0.0298mol), and DIEA (10 ml, 0.075 mol) in THF (80 ml). The reaction wasallowed to stir overnight at room temperature. The solvent wasconcentrated and the resulting material was redissolved in ethyl acetateand extracted with 1N HCl followed by brine. The organic layer wasconcentrated. Purification by flash chromatography (4:1 hexane:ethylacetate) gave the Weinreb amide (7.23 g, 66%). C₂₀H₃₁NO₅ (MW=365.22);mass spectroscopy (MH⁺)=366.22

Step C

A THF solution (50 ml) of the Weinreb amide from Step B (3.4 g, 0.0093mol) was cooled to −78° C. and methyl magnesium bromide (3.0 M in ether,15 ml, 0.046 mol) was added to the solution. After stirring for twohours, 1N HCl was added to quench the reaction. The reaction mixture wasextracted with ether. The ethereal layer was concentrated. Purificationby flash chromatography (9:1 hexanes:ethyl acetate) yielded the methylketone as a colorless oil (1.77 g, 60%). C₁₉H₂₈O₄ (MW=320.20); massspectroscopy (MH⁺)=321.0

Step D

The methyl ketone from Step C (1.77 g, 0.0055 mol) was combined withpotassium cyanide (0.792 g, 0.0122 mol) and ammonium carbonate (2.65 g,0.0277 mol) in 1:1 methanol: water (20:20 ml) and stirred overnight at50° C. The reaction mixture was poured into water and extracted withethyl acetate. The organic layer was washed with brine then concentratedto afford the hydantoin as a white solid (2.11 g, 99%) which was carriedforth without further purification. C₂₁H₃₀N₂O₅ (MW=390.22); massspectroscopy (MH⁺)=391.3

Step E

The hydantoin from Step D (0.600 g, 0.0015 mol) was dissolved in DMF (10ml) and treated with K₂CO₃ (0.849 g, 0.0060 mol) and magnesium sulfate(0.271 g, 0.0023 mol) followed by 4-ethyl benzyl chloride (0.252 ml,0.00169 mol). The reaction was stirred overnight at room temperature.The reaction mixture was poured into 5N HCl and extracted with ethylacetate (2×). The organic layer was concentrated. Purification of thecrude material by flash chromatography (2:1 ethyl acetate:hexanes) gavethe alkylated hydantoin as a colorless oil (0.752 g, 98%). C₃₀H₄₀N₂O₅(MW=508.29); mass spectroscopy (MH⁺)=509.3

Step F

The ester from Step E (0.752 g, 0.00148 mol) was dissolved indichloromethane (20 ml) and treated with trifluoroacetic acid (0.570 ml,0.0074 mol). The reaction was stirred overnight. The solution wasconcentrated. Purification of the crude material by flash chromatography(2:1 hexanes:ethyl acetate) afforded the desired product as a whitesolid (0.358 g, 54%). C₂₆H₃₂N₂O₅ (MW=452.23); mass spectroscopy(MH⁺)=453.3

Step A

A THF (15 mL) solution of the hydantoin from Example 22, Step A (855.1mg, 1.34 mmol) under an atmosphere of nitrogen was treated with BH₃-THF(1.0 M in THF, 13.5 mL, 13.5 mmol). The reaction mixture was stirred atroom temperature for 3 hours then cooled to 0° C. and carefully treatedwith saturated aqueous sodium bicarbonate (25 mL). After 2 hr additionalbicarbonate (20 mL) was added along with H₂O (100 mL). The resultingsolution was extracted with ethyl acetate (2×100 mL). The combinedorganic extracts were dried over Na₂SO₄ and concentrated. Purificationby chromatography (2:1 hexanes:ethyl acetate) gave the desired productas a colorless oil (595.4 mg, 71%). C₃₉H₄₆N₂O₅ (MW=622.81); massspectroscopy: (MH⁺)=623.3

Step B

A TFA solution (10 mL) of the product from Step A (595.4 mg, 0.956 mmol)was treated with triethylsilane (618 mL, 3.8 mmol) and stirred at roomtemperature for 1.5 hour. The reaction mixture was concentrated and theresidue diluted with 0.5 N NaOH (50 mL). The aqueous solution was washedwith diethyl ether (50 mL), acidified with 5 N HCl, then extracted withethyl acetate (2×50 mL). The combined organic extracts were dried overNa₂SO₄ and concentrated to afford the desired carboxylic acid as afoam-like solid (417.8 mg, 98%). C₂₇H₃₀N₂O₄ (MW=446.55); massspectroscopy: (MH⁺)=447.2, (MH⁻)=445.4

Step A

4-Hydroxyphenethyl alcohol (15.0 g, 109 mmol) and ethyl2-bromoisobutyrate (24 ml, 163.5 mmol) were stirred together in DMF (250ml). Potassium carbonate (44.9 g, 325 mmol) and magnesium sulfate (13.1g, 109 mmol) added and the mixture was stirred at 75° C. overnight. Thereaction mixture was cooled, filtered over Celite, washing the filtercake with ethyl acetate. The combined filtrates were diluted with ethylacetate, washed with water and 2N hydrochloric acid, dried over sodiumsulfate, filtered and concentrated. The obtained residue was dissolvedin ether and washed with 2N sodium hydroxide and aqueous brine, driedover sodium sulfate. Evaporation of the solvent and subsequentpurification by flash chromatography (hexanes:ethyl acetate) gave thedesired product (11.8 g). C₁₄H₂₀O₄ (MW=252.3); MS (M+, 253.1)

Step B

Carbonyldiimidazole (10.0 g, 61.7 nmol) was stirred in methylenechloride (100 ml) and benzylamine (13.5 ml, 23.4 mmol, in CH₂Cl₂, 20 ml)was added dropwise. An ice bath was placed under the flask during theaddition. After complete addition the mixture was allowed to stirovernight at ambient temperature. The resulting solid was washed withether and filtered to yield the desired product as a white solid (13.9g). C₁₅H₁₆N₂O (MW=240.3); MS (M+, 241.0)

Step C

The product from Example 137, Step B (10.0 g, 41.7 mmol) was stirred indioxane and oxalyl chloride (3.6 ml, 41.7 mmol) was added via syringe.The mixture was heated to 75° C. overnight. Evaporation of the solventand washing the obtained solid with ether gave the desired product as awhite solid (12.1 g). C₁₇H₁₄N₂O₃ (MW=294.3); 1 NMR

Step D

The product from Example 137, Step C (2.0 g, 6.8 mmol) was stirred inTHF (50 ml) and methanol (30 ml). Sodium borohydride was added andstirred for 5 minutes. Water (1 ml) and concentrated hydrochloric acid(1 ml) were added then allowed to stand over sodium sulfate overnight.Evaporation of the solvent gave a residue that was dissolved in waterand ethyl acetate. Layers were separated and the organic layer waswashed with aqueous brine and dried over sodium sulfate. Evaporation ofthe solvent gave the desired product (2.0 g). C₁₇H₁₆N₂O₃ (MW=296.3); 1NMR

Step E

The products from Example 137, Step A (1.7 g, 6.8 mmol) and Step D (1.0g, 3.4 mmol) were stirred together in acetonitrile (10 ml) withp-toluenesulfonic acid (0.1 g, 0.5 mmol) and heated to 80° C. for 6hours. The resulting mixture was concentrated and methylene chlorideadded. This was washed with water and aqueous brine then dried oversodium sulfate. Evaporation of the solvent and subsequent purificationby flash chromatography (hexanes/ethyl acetate) gave the desired product(0.8 g). C₃₁H₃₄N₂O₆ (MW 530.6); 1 NMR

Step F

The product from Example 137, Step E (0.25 g, 0.47 mmol) was dissolvedin methanol (2 ml), added to lithium hydroxide (0.02 g, 11.0 mmol, inwater, 5 ml) and heated to 50° C. for 1 hour, then stirred over two daysat ambient temperature. Hydrolysis completed by heating to reflux for 1hour. The reaction was added to water and extracted with ether. Theaqueous layer was acidified with concentrated hydrochloric acid andextracted twice with ethyl acetate. The organic layers were combined,washed with aqueous brine and dried over sodium sulfate. Evaporation ofthe solvent gave the desired product (0.19 g). C₂₉H₃₀N₂O₆ (MW=502.6); MS(M−, 501.1)

Example 138 1-Isocyanatomethyl-4-methyl-benzene

A mixture of p-methyl benzylamine (25 g, 0.21 mol) in CH₂Cl₂ (200 mL)and aqueous saturated solution of sodium bicarbonate (200 mL) was cooledto 0° C. and then treated dropwise with a 20% solution of phosgene intoluene (100 mL). The reaction was stirred at room temperature for 20minutes and then the organic layer removed and the aqueous layerback-extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄) and thesolvent removed in vacuo to give 20.6 g1-isocyanatomethyl-4-methyl-benzene that was utilized directly in thenext reaction without purification.

Step B 1-(4-Methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea

A 0° C. slurry of α-amino-γ-butyrolactone hydrobromide (25 g, 0.137 mol)in THF (200 mL) was combined with 1-isocyanatomethyl-4-methyl-benzene(20.6 g, 0.139 mol) and then treated dropwise withN,N-diisopropylethylamine (19.5 g, 0.151 mol). The reaction mixture wasstirred for at room temperature for 2 h. The solvent was removed invacuo to give 48.5 g crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea that was utilized directly in the next reaction withoutpurification. MS (ES”) Calc'd for C₁₃H₁₇N₂O₃ (M+1) 249. Found m/z 249(100%). ¹H NMR.

Step C 5-(2-Hydroxy-ethyl)-3-(4-methyl-benzyl)-imidazolidine-2,4-dione

A solution of crude 1-(4-methyl-benzyl)-3-(2-oxo-tetrahydro-furan-3-yl)-urea (48.5 g, assume 0.137 mol) in MeOH (1.5 L) was treatedwith sodium methoxide (21.1 g, 0.391 mol) and heated to reflux under N₂for 2 h until done by thin layer chromatography (9:1 CH₂Cl₂:MeOH). Thereaction was cooled and the solvent removed in vacuo to give a residuethat was combined with aqueous 1 N HCl (640 mL) and extracted withEtOAc. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford 24.72 g (73%) of crude5-(2-hydroxy-ethyl)-3-(4-methyl-benzyl)-imidazolidine-2,4-dione as ayellow solid which was carried on in the next step without purification.MS (ES⁺) Calc'd for C₁₃H₁₇N₂O₃ (M+1) 249. Found m/z 249 (100%). ¹H NMR.

Step D 5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-imidazolidine-2,4-dione

A solution of crude 5-(2-hydroxy-ethyl)-3-(4-methyl-benzyl)-imidazolidine-2,4-dione (24.68 g, 99.4 mmol) and imidazole (10.15 g,0.149 mol) in DMF (250 mL) was treated dropwise withtert-butyldiphenylsilyl chloride (27.37 g, 99.6 mmol) and then stirredat room temperature under N₂ for 7 h. The reaction was worked upextractively with aqueous 1 N HCl (300 mL), diethyl ether and brine andthe organic layer was dried (MgSO₄) and the solvent removed in vacuo togive crude product which was purified by flash chromatography using agradient of 5:1 to 2:1 hexanes:EtOAc to afford 23.82 g (49%) of5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-imidazolidine-2,4-dione. MS (ES⁺) Calc'd for C₂₉H₃₅N₂O₃Si (M+1)487. Found m/z 487 (100%). ¹H NMR.

Step E 5-[2-(tert-Butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione

A 0° C. solution of 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-imidazolidine-2,4-dione (14.26 g, 29.3 mmol)in DMF (250 mL) was treated with sodium hydride (60% dispersion, 1.29 g,32.2 mmol) and warmed to room temperature and stirred under N₂ for 30minutes. The resultant mixture was cooled to 0° C. and then treated with1-propyl iodide (5.47 g, 32.2 mmol) and then warmed to room temperatureand stirred for 3 h. The reaction was quenched with aqueous 1 N HCl (60mL) and then worked up extractively with diethyl ether and water. Theorganic layer was dried (MgSO₄) and the solvent removed in vacuo to givecrude product that was purified by flash chromatography using 6:1hexanes:acetone to afford 14.8 g (96%) 5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione. MS (ES⁺) Calc'd for C₃₂H₄₀N₂O₃Si (M +1) 529.Found m/z 529 (100%). ¹H NMR.

Step F4-(2-Hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one

A solution of5-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione(14.71 g, 27.8 mmol) in EtOH (500 mL) was treated with sodiumborohydride (15.78 g, 0.417 mol) in three portions over 6 h and stirredat room temperature under N₂ for an additional 16 h. The thick reactionmixture was cooled in an ice bath and slowly quenched with aqueous 1 NHCl (˜1 L) over a 1 h period. The reaction mixture was then worked upextractively with EtOAc, water and brine and the organic layer dried(MgSO₄) and the solvent removed in vacuo to give 16.79 g crude4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-onethat was de-silylated immediately.

The4-[2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one(16.79 g, assumed 27.8 mmol) was dissolved in THF (160 mL) and thentreated with a 1 M solution of tetrabutylammonium fluoride in THF (55.6mL, 55.5 mmol) and the reaction stirred at room temperature under N₂ for20 minutes. The reaction was worked up extractively with EtOAc and waterand the organic layer dried (MgSO₄) and the solvent removed in vacuo togive crude product that was purified by flash chromatography using 3% ofMeOH in CH₂Cl₂ to afford 4.65 g (61%)4-(2-hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one. MS (ES⁺) Calc'd for C₁₆H₂₃N₂O₂ (M+1) 275. Found m/z 275(100%). ¹H NMR.

Step G Toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethylester

A solution of4-(2-hydroxy-ethyl)-1-(4-methyl-benzyl)-3-propyl-1,3-dihydro-imidazol-2-one(0.126 g, 0.459 mmol), pyridine (0.146 g, 1.85 mmol) and 4-dimethylamino pyridine (0.017 g, 0.139 mmol) in CH₂Cl₂ (10 mL) was treated withp- toluenesulfonic anhydride (0.240 g, 0.735 mmol) and the reactionstirred at room temperature for under N₂ for 1.5 h. The reaction mixturewas washed with aqueous 1 N HCl (4 mL), the organic layer was dried(MgSO₄), and the solvent removed in vacuo to afford crude product thatwas purified by flash chromatography using 100% CH₂Cl₂ then 2.5% MeOH inCH₂Cl₂ to afford 0.194 g (98%) toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethyl ester. MS(ES⁺) Calc'd for C₂₃H₂₉N₂O₄S (M+1) 429. Found m/z 429 (100%). ¹H NMR.

Step H2-Methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionicacid

A mixture of toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethylester (0.194 g, 1.51 mmol), 2-(4-hydroxy-phenoxy)-2-methyl- propionicacid ethyl ester (0.088 g, 0.392 mmol) and CS₂CO₃ (0.156 g, 0.478 mmol)in DMF (15 mL) was heated at 55° C. for under N₂ for 16 h. The reactionmixture was cooled to room temperature, quenched with aqueous 1 N HCl (2mL), and worked up extractively with EtOAc and water. The organic layerwas dried (MgSO₄) and the solvent removed in vacuo to afford crudeproduct that was purified by flash chromatography using a gradient of4:1 to 1:1 hexanes:acetone to afford 0.036 g (19%)2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionicacid ethyl ester.

The2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionic acid ethyl ester (0.036 g, 0.075 mmol) was combined withaqueous 5 N NaOH (0.15 mL) in EtOH (5 mL) and heated to reflux under N₂for 1 h. The reaction was cooled and the solvent removed in vacuo togive a residue that was acidified with aqueous 1 N HCl (1 mL). Themixture was extracted with Et₂O and water, the organic layer dried(MgSO₄), and the solvent removed in vacuo to afford 0.024 g (71%)2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenoxy)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₆H₃₃N₂O₅ [M+0.1] 453.2389,found 453.2387. ¹H NMR.

Example 1392-Methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid

A mixture of toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethylester (0.079 g, 0.184 mmol),3-(4-hydroxy-phenyl)-2-methoxy-2-methyl-propionic acid ethyl ester(0.038 g, 0.169 mmol) and K₂CO₃ (0.047 g, 0.340 mmol) in EtOH (8 mL) washeated at 75° C. under N₂ for 16 h. The reaction mixture was cooled toroom temperature and quenched with aqueous 1 N HCl (1 mL). The solventwas removed in vacuo to give a residue that was diluted with water andextracted with EtOAc. The organic layer was dried (MgSO₄) and thesolvent removed in vacuo to afford crude product that was purified byflash chromatography using a 2:1 hexanes:acetone to afford 0.036 g (44%)2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester.

The2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (0.015 g, 0.031 mmol) was combined withaqueous 5 N NaOH (0.1 mL) in EtOH (3 mL) and heated to reflux under N₂for 1 h. The reaction was cooled and the solvent removed in vacuo togive a residue that was acidified with aqueous 1 N HCl (3 mL). Themixture was extracted with Et₂O and water, the organic layer dried(MgSO₄), and the solvent removed in vacuo to afford 0.015 g (100%)2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-propionic acid. MS (ES⁺) m/z calcd for C₂₆H₃₂N₂O₅ [M+1] 453, found 453.¹H NMR.

Example 1402-Methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid

A mixture of toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethylester (0.029 g, 0.0677 mmol),3-(4-Hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester(0.018 g, 0.0599 mmol) and Cs₂CO₃ (0.024 g, 0.0736 mmol) in DMF (3 mL)was heated at 55° C. under N₂ for 16 h. The reaction mixture was cooledto room temperature and quenched with aqueous 1 N HCl (0.3 mL) and thenwas diluted with water and extracted with Et₂O. The organic layer wasdried (MgSO₄) and the solvent removed in vacuo to afford crude productthat was purified by flash chromatography using a gradient of 4:1 tohexanes:EtOAc to 2:1 EtOAc:hexanes to afford 0.011 g (32%)2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester.

The2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid ethyl ester (0.0 llg, 0.020 mmol) was combined with aqueous 5 NNaOH (0.2 mL) in EtOH (3 mL) and heated to reflux under N₂ for 1 h. Thereaction was cooled and the solvent removed in vacuo to give a residuethat was acidified with aqueous 1 N HCl (2 mL). The mixture wasextracted with Et₂O and water, the organic layer dried (MgSO₄), and thesolvent removed in vacuo to afford 0.007 g (67%)2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid.HRMS (ES⁺) m/z exact mass calcd for C₃₂H₃₇N₂O₅ (M+1] 529.2702, found529.2715. ¹H NMR.

Example 141 Step A1-(3,4-Dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one

A 0° C. solution of 3-(3,4-dimethyl-benzyl)-5-[3-(4-methoxy-phenyl)-propyl]-1-propyl-imidazolidine-2,4-dione (0.155 g, 0.379 mmol)in THF (6 mL) was treated dropwise with a 3 molar solution of methylmagnesium bromide in Et₂O (0.76 mL, 2.28 mmol) and then stirred at 0° C.under N₂ for 1 h. The reaction was quenched with 1 N HCl (5 mL) andstirred at room temperature for 15 minutes to effect elimination andthen was worked up extractively with EtOAc and water. The organic layerdried (MgSO₄), and the solvent removed in vacuo to afford 0.155 g (100%)1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification. MS (ES⁺) Calc'dfor C₂₋₆H₃₅N₂O₂ (M+1) 407. Found m/z 407 (100%). ¹H NMR.

Step B2-(4-{3-[1-(3,4-Dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester

A 0° C. solution of 1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one (0.145 g,0.357 mmol) in CH₂Cl₂ (6 mL) was treated dropwise with BBr₃ (0.10 mL,1.06 mmol) and then stirred at 0° C. under N₂ for 30 minutes. Thereaction was diluted with Et₂O and then quenched with ice and thenwater. The organic layer was dried (MgSO₄), and the solvent removed invacuo to afford 0.169 g (100%)1-(3,4-dimethyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification.

The crude 1-(3,4-dimethyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one (0.169 g)was combined with ethyl 2-bromoisobutyrate (0.366 g, 1.87 mmol), MgSO₄(0.043 g, 0.357 mmol) and 325 mesh K₂CO₃ (0.197 g, 1.43 mmol) in ethanol(8 mL) and heated a 75° C. for 16 h under N₂. The reaction was cooledand the solvent removed in vacuo. The residue was acidified with 1 N HCl(10 mL) and extracted with EtOAc and water. The organic layer was dried(MgSO₄), and the solvent removed in vacuo to afford crude product thatwas purified by flash chromatography using 2:1 to hexanes:acetone toafford 0.124 g (69%)2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid ethyl ester. MS (ES⁺) Calc'd for C₃₁H₄₃N₂O₄ (M+1) 507. Found m/z507 (100%). ¹H NMR.

Step C2-(4-{3-[1-(3,4-Dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid

A solution of2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid ethyl ester (0.124 g, 0.244 mmol) in EtOH (10 mL) was treated withaqueous 5 N NaOH (0.5 mL) and heated to reflux under N₂ for 1 h. Thereaction was cooled and the solvent removed in vacuo to give a residuethat was acidified with aqueous 1 N HCl. The mixture was extracted withEt₂O and water, the organic layer dried (MgSO₄), and the solvent removedin vacuo to afford 0.104 g (89%)2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-methyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid. HRMS (ES⁺) m/z exact mass calcd for C₂₉H₃₉N₂O₄ [M+1]479.2910, found 479.2917. ¹H NMR.

Example 1422-(4-{3-[1-(3,4-Dimethyl-benzyl)-5-ethyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized with ethyl magnesium bromide toafford2-(4-{3-[1-(3,4-dimethyl-benzyl)-5-ethyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₃₀H₄₁N₂O₄ [M+1] 493.3066,found 493.3079. ¹H NMR.

Cyclic Urea Experimentals

General Procedure

Step A2-(4-{2-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

A mixture of toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.10 g, 7.41mmol), 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester (1.50g, 6.69 mmol) and CS₂CO₃ (2.62 g, 8.04 mmol) in DMF (70 mL) was heatedat 65° C. for under N₂ for 16 h. The reaction mixture was cooled to roomtemperature, quenched with aqueous 1 N HCl (25 mL), and worked upextractively with EtOAc and water. The organic layer was dried (MgSO₄)and the solvent removed in vacuo to afford crude product that waspurified by flash chromatography using 5:1 hexanes:acetone to afford2.92 g (93%)2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester. MS (ES⁺) Calc'd for C₃₆H₄₇N₂O₆ (M+1) 603. Found m/z603 (100%). ¹H NMR.

Step B2-Methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionicacid ethyl ester

A mixture of 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester(2.72 g, 5.78 mmol) and triethylsilane (1.34 g, 11.5 mmol) was treatedwith trifluoroacetic acid (70 mL) and stirred at room temperature underN₂ for 5 h. The reaction mixture was diluted with water and thenextracted with ethyl acetate. The organic layer was dried (MgSO₄) andthe solvent removed in vacuo to afford crude product that was purifiedby flash chromatography using 98:2 CH₂Cl₂:MeOH to afford 2.40 g (100%)2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid ethyl ester.R_(f)=0.09 (1:1 hexanes:acetone); MS (ES⁺) Calc'd for C₁₈H₂₇N₂O₅ (M+1)351. Found m/z 351 (100%). ¹H NMR.

Step C 2-(4-{2-[1-(4-Methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester

A solution of2-methyl-2-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionicacid ethyl ester (0.143 g, 0.408 mmol) in dry DMF (4 mL) was treated a60% suspension of NaH (0.033 g, 0.825 mmol) and the resultant mixturewas stirred at room temperature for 20 minutes under N₂. The reactionmixture was cooled to 0° C. and then treated with p-methylsulfonylbenzyl chloride and then warmed to room temperature andstirred for 16 h. The reaction was acidified with aqueous 1 N HCl (4mL), diluted with water and extracted with Et₂O. The organic layer wasdried (MgSO₄) and the solvent removed in vacuo to afford crude productthat was purified by column chromatography using a gradient of 4:1 to1:1 hexanes:acetone to afford 0.090 g (42%)2-(4-{2-[1-(4-methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester. R_(f)=0.40 (1:1 hexanes:acetone) MS (ES⁺) Calc'd forC₂₆H₃₅N₂O₇S (M+1) 518. Found m/z 518 (100%). ¹H NMR.

Step D 2-(4-{2-[1-(4-Methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

A solution of2-(4-{2-[1-(4-methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester (0.087 g, 0.168 mmol) in ethanol (8 mL) wastreated with aqueous 5 N NaOH (1 mL) and heated to reflux 1 h. Thereaction mixture was cooled, the solvent removed in vacuo. The resultantresidue was acidified with aqueous 1 N HCl (5 mL) and extracted withCH₂Cl₂. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford 0.043 g (52%) 2-(4-{2-[1-(4-methanesulfonyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}1-phenoxy)-2-methyl-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₄H₃₁N₂O₇S 491.1852, found491.1879. ¹H NMR.

Example 1432-(4-{2-[1-(4-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

A solution of 2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester(0.198 g, 0.421 mmol) in ethanol (10 mL) was treated with aqueous 5 NNaOH (1 mL) and heated to reflux 1.5 h. The reaction mixture was cooled,the solvent removed in vacuo. The resultant residue was acidified withaqueous 1 N HCl (10 mL) and extracted with Et₂O. The organic layer wasdried (MgSO₄) and the solvent removed in vacuo to afford 0.147 g (79%)2-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. MS (ES⁺)Calc'd for C₂₄H₃₁N₂O₆ (M+1) 443. Found m/z 443 (100%). ¹H NMR.

Example 144 (R)-2-Methyl-2-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionic acid

The procedures herein were utilized with 4-trifluoromethylbenzyl bromideto prepare(R)-2-methyl-2-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionic acid. HRMS (ES⁺) m/z exactmass calcd for C₂₄H₂₈N₂O₅F₃ 481.1950, found 481.1960. ¹H NMR.

Example 145 (R)-2-(4-{2-[1-(3,4-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized with 3,4-difluorobenzyl bromide toprepare(R)-2-(4-{2-[1-(3,4-difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES⁺) m/z exact mass calcd for C₂₃H₂₇N₂O₅F₂449.1888, found 449.1888. ¹H NMR.

Example 146 (R)-2-Methyl-2-{4-[2-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid

The procedures herein were utilized with 2-(chloromethyl)quinoline toprepare(R)-2-methyl-2-{4-[2-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid. HRMS (ES⁺) m/z exact mass calcd forC₂₆H₃₀N₃O₅ 464.2185, found 464.2193. ¹H NMR.

Example 147 (R)-2-(4-{2-[1-(3,5-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized with 3,5-difluorobenzyl bromide toprepare(R)-2-(4-{2-[1-(3,5-difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES⁺) m/z exact mass calcd for C₂₃H₂₇N₂O₅F₂449.1888, found 449.1913. ¹H NMR.

Example 148 (R)-2-(4-{2-[1-(3-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized with 3-methoxybenzyl bromide toprepare(R)-2-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES⁺) m/z exact mass calcd for C₂₄H₃₁N₂06 443.2182,found 443.2182. ¹H NMR.

Example 149 (R)-2-(4-{2-[1-(4-Chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized with 4-chlorobenzyl bromide toprepare(R)-2-(4-{2-[1-(4-chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES⁺) m/z exact mass calcd for C₂₃H₂₈N₂O₅Cl447.1687, found 447.1667. ¹H NMR.

Example 150 (R)-2-Methyl-2-{4-[2-(3-methyl-2-oxo-1-pyridin-2-ylmethyl-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid

The procedures herein were utilized with 2-picolyl chloridehydrochloride to prepare(R)-2-methyl-2-{4-[2-(3-methyl-2-oxo-1-pyridin-2-ylmethyl-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₂H₂₈N₃O₅ 414.2029, found414.2028. ¹H NMR.

Example 151 Step A[1-(3,4-Dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methylester

A solution of (2,5-dioxo-imidazolidin-4-yl)-acetic acid methyl ester(6.0 g, 34.8 mmol) in DMF (240 mL) was treated with 3,4-dimethyl benzylbromide (5.93 g, 38.3 mmol), MgSO₄ (8.40 g, 60.8 mmol) and then 325 meshK₂CO₃ (9.15 g, 66.2 mmol) at 0° C. The resultant mixture was warmed toroom temperature under N₂ and then heated at 50° C. for 5 h. Thereaction mixture was cooled to room temperature then filtered, and thenaqueous 1N HCl (140 mL) was added to the filtrate. The filtrate wasextracted with EtOAc and the organic layer dried (MgSO₄). The solventwas removed in vacuo to give 11.43 g crude product which was purified byflash chromatography using 3:1 hexanes:acetone to give 6.35 g of productthat was triturated in Et₂O/hexanes and filtered to give 2.24 g (22%)[1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methylester. MS (ES⁺) Calc'd for C₁₅H₁₉N₂O₄ (M+1) 291. Found m/z 291 (100%).¹H NMR.

Step B [1-(3,4-Dimethyl-benzyl)-3-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester

A 0° C. solution of compound[1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methylester (2.24 g, 7.71 mmol) in DMF (30 mL) was treated with sodium hydride(60% dispersion, 0.37 g, 9.25 mmol) and warmed to room temperature andstirred under N₂ for 20 minutes. The resultant mixture was cooled to 0°C. and then treated with 4-methoxybenzyl chloride (2.41 g, 15.4 mmol)and then warmed to room temperature and stirred for 16 h. The reactionwas quenched with 25 mL of aqueous 1 N HCl and then worked upextractively with Et₂O and water. The organic layer was dried (MgSO₄)and the solvent removed in vacuo to give crude product that was purifiedby flash chromatography using a gradient of 5:1 hexanes:actetone toafford 3.23 g (100%)[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-acetic acid methyl ester. MS (ES⁺) Calc'd forC₂₃H₂₆N₂O₅ (M+1) 411. Found m/z. 411 (100%). ¹H NMR.

Step C 1-(3,4-Dimethyl-benzyl)-4-(2-hydroxy-ethyl)-3-(4-methoxy-benzyl)-imidazolidin-2-one

A solution of[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2,5-dioxo-imidazolidin-4-yl]-aceticacid methyl ester (3.22 g, 7.84 mmol) in methanol (50 mL) was treatedwith aqueous 5 N NaOH (25.7 mL) and heated to reflux 1.5 h. The reactionmixture was cooled, the solvent was removed in vacuo. The resultantresidue was acidified with aqueous 1 N HCl (200 mL) and extracted withEt₂O and water. The organic layer was dried (MgSO₄) and the solvent wasremoved in vacuo to afford 3.18 g (100%) of acid that was utilizedwithout purification. A solution of crude acid (3.18 g, assume 7.84mmol) in THF (50 mL) was treated dropwise with 1 M solution ofborane-THF complex in THF (47 mL, 47 mmol) and then stirred at roomtemperature under N₂ for 16 h. The reaction was quenched with methanol(30 mL) and stirred at room temperature for 30 minutes. The solvent wasremoved in vacuo to give crude product that was purified by flashchromatography using 3:1 hexanes:acetone to afford 1.89 g (65%)1-(3,4-dimethyl-benzyl)-4-(2-hydroxy-ethyl)-3-(4-methoxy-benzyl)-imidazolidin-2-one.MS (ES⁺) Calc'd for C₂₂H₂₈N₂O₃ (M+1) 369. Found m/z 369 (100%). ¹H NMR.

Step D Toluene-4-sulfonic acid2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethylester

A solution of1-(3,4-dimethyl-benzyl)-4-(2-hydroxy-ethyl)-3-(4-methoxy-benzyl)-imidazolidin-2-one(1.89 g, 5.13 mmol), pyridine (1.42 g, 17.9 mmol) and 4-dimethyl aminopyridine (0.188 g, 1.54 mmol) in CH₂Cl₂ was treated with p-toluenesulfonic anhydride (2.68 g, 8.21 mmol) and the reaction stirredat room temperature for under N₂ for 1.5 h. The reaction mixture waswashed with aqueous 0.5 N HCl (100 mL), the organic layer was dried(MgSO₄), and the solvent removed in vacuo to afford crude product thatwas purified by flash chromatography using 3:1 hexanes:actetone toafford 2.57 g (96%) toluene-4-sulfonic acid 2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethyl ester. MS(ES⁺) Calc'd for C₂₉H₃₄N₂O₅S (M+1) 523. Found m/z 523 (100%). ¹H NMR.

Step E 2-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester

A mixture of toluene-4-sulfonic acid 2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethyl ester (2.54g, 4.86 mmol), 2-(4-hydroxy-phenoxy)-2-methyl- propionic acid ethylester (0.99 g, 4.01 mmol) and CS₂CO₃ (1.73 g, 5.31 mmol) in DMF (60 mL)was heated at 55° C. for under N₂ for 16 h. The reaction mixture wascooled to room temperature, quenched with aqueous 1 N HCl (25 mL), andworked up extractively with EtOAc and water. The organic layer was dried(MgSO₄) and the solvent removed in vacuo to afford crude product thatwas purified by flash chromatography using 4:1 hexanes:acetone to afford2.51 g (99%)2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester. MS (ES⁺) Calc'd for C₃₄H₄₃N₂O₆ (M+1) 575. Found m/z575 (100%). ¹H NMR.

Step F2-(4-{2-[1-(3,4-Dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester

A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-(4-methoxy-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl- propionicacid ethyl ester (2.51 g, 4.36 mmol) in trifluoroacetic acid (70 mL) wasstirred at room temperature under N₂ for 1 h. The reaction was dilutedwith water, and extracted with Et₂O. The organic layer was dried (MgSO₄)and the solvent removed in vacuo to afford crude product that waspurified by flash chromatography using 98:2 CH₂Cl₂:MeOH to afford 1.20 g(60%)2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester. MS (ES⁺) Calc'd for C₂₆H₃₅N₂O₅ (M+1) 455. Found m/z455 (100%). ¹H NMR.

Step G2-(4-{2-[1-(3,4-Dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester(0.087 g, 0.191 mmol) in ethanol (8 mL) was treated with aqueous 5 NNaOH (0.4 mL) and heated to reflux 1.5 h. The reaction mixture wascooled, the solvent removed in vacuo. The resultant residue wasacidified with aqueous 1 N HCl (5 mL) and extracted with Et₂O. Theorganic layer was dried (MgSO₄) and the solvent removed in vacuo toafford 0.059 g (72%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. HRMS (ES⁺)m/z exact mass calcd for C₂₄H₃₁N₂O₅ [M+1] 427.2233, found 427.2232. ¹HNMR.

Example 152 Step A 2-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester

A solution of 2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester(0.128 g, 0.280 mmol) in DMF (4 mL) was treated with 60% oil suspensionof NaH (0.028 g, 0.70 mmol) and stirred at room temperature under N₂ for15 minutes. The reaction was cooled to 0° C. and treated withiodomethane (0.16 g, 1.13 mmol) and then warmed to room temperature andstirred for 1 h. The reaction was quenched with 1 N HCl (3 mL) andworked up extractively with Et₂O and water. The organic layer was dried(MgSO₄) and the solvent removed in vacuo to afford crude product thatwas purified by flash chromatography using 5:1 hexanes:acetone to afford0.098 g (74%) 2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid ethyl ester.MS (ES⁺) Calc'd for C₂₇H₃₇N₂O₅ (M+1) 469. Found m/z 469 (100%). ¹H NMR.

Step B 2-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

A solution of2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid ethyl ester (0.098 g, 0.209 mmol) in ethanol (8 mL) was treatedwith aqueous 5 N NaOH (0.5 mL) and heated to reflux 1 h. The reactionmixture was cooled, the solvent removed in vacuo. The resultant residuewas acidified with aqueous 1 N HCl (5 mL) and extracted with Et₂O. Theorganic layer was dried (MgSO₄) and the solvent removed in vacuo toafford 0.050 g (54%)2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₅H₃₃N₂O₅ [M+11 4.41.2389,found 441.2390. ¹H NMR.

Example 1532-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-ethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

The procedures herein utilized with ethyl iodide to afford2-(4-{2-[1-(3,4-dimethyl-benzyl)-3-ethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. MS (ES⁺) Calcld for C₂₆H₃₅N₂O₅ (M+1) 455. Found m/z 455 (100%). ¹HNMR.

Example 154 2-(4-{2-[1-(3,4-Dimethyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein utilized with propyl iodide to afford2-(4-{2-[1-(3,4-dimethyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid. MS (ES⁺)Calc'd for C₂₇H₃₇N₂O₅ (M+1) 469. Found m/z 469 (100%). ¹H NMR.

Example 155 (R)-2-Methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionic acid

The procedures herein were utilized to prepare2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₆H₃₅N₂O₅ [M+1] 455.2546,found 455.2565. ¹H NMR.

Example 156 (R)-2-Methyl-2-(4-{2-[3-methyl-1-(4-methyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionic acid

The procedures herein were utilized to prepare2-methyl-2-(4-{2-[3-methyl-1-(4-methyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionic acid. HRMS (ES⁺) m/z exactmass calcd for C₂₄H₃₁N₂O₅ [M+1] 427.2233, found 427.2233. ¹H NMR.

Example 1572-(4-{2-[1-(4-tert-Butyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

The procedures herein were utilized to prepare2-(4-{2-[1-(4-tert-butyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₆H₃₅N₂O₅ [M+1] 455.2546,found 455.2538. ¹H NMR.

Example 158 2-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized to prepare2-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₇N₂O₅ [M+1] 469.2702,found 469.2690. ¹H NMR.

Example 1592-(4-{2-[1-(4-tert-Butyl-benzyl)-3-ethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid

The procedures herein were utilized to prepare2-(4-{2-[1-(4-tert-butyl-benzyl)-3-ethyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₈H₃₉N₂O₅ (M+1) 483. Found m/z 483 (100%). ¹HNMR.

Example 160 2-(4-{2-[1-(4-tert-Butyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionic acid

The procedures herein were utilized to prepare2-(4-{2-[1-(4-tert-butyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₉H₄₁N₂O₅ (M+1) 497. Found m/z 497 (100%). ¹HNMR.

Example 161 2-Methyl-2-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid

The procedures herein were utilized to prepare2-methyl-2-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid. MS (ES⁺) Calc'd for C₂₆H₂₉N₂O₅ (M+1)449. Found m/z 449 (100%). ¹H NMR.

Example 162 2-Methyl-2-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid

The procedures herein were utilized to prepare2-methyl-2-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid. MS (ES⁺) Calc'd for C₂₇H₃₁N₂O₅(M+1) 463. Found m/z 463 (100%). ¹H NMR.

Example 163 2-Methyl-2-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-3-propyl-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionic acid

The procedures herein were utilized to prepare2-methyl-2-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-3-propyl-imidazolidin-4-yl)-ethoxy]-phenoxy}-propionicacid. MS (ES⁺) Calc'd for C₂₉H₃₅N₂O₅ (M+1) 491. Found m/z 491 (100%). ¹HNMR.

Example 164 2,2-Dimethyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The procedures herein were utilized to prepare2,2-dimethyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₇N₂O₄ [M+1] 453.2753,found 453.2754. ¹H NMR.

Example 165 2-Methyl-2-(3-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionic acid

The procedures herein were utilized to prepare2-methyl-2-(3-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₆H₃₄N₂O₅ [M+1] 455.2546,found 455.2549. ¹H NMR.

Example 1662-Methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid

The procedures herein were utilized to prepare2-methoxy-2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid. HRMS (ES⁺) m/z exactmass calcd for C₂₇H₃₆N₂O₅ [M+1) 469.2702, found 469.2709. ¹H NMR.

Example 1672-(4-{2-[1-(4-Methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-benzyl)-butyricacid

The procedures herein were utilized to prepare2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-benzyl)-butyricacid. HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₆N₂O₄ [M+1] 453.2753,found 453.2749. ¹H NMR.

Example 1684-{2-[1-(4-Methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-benzoicacid

The procedures herein were utilized to prepare4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-benzoicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₃H₂₉N₂O₄ [M+1] 397.2127,found 397.2112. ¹H NMR.

Example 169(4-{2-[1-(4-Methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-aceticacid

The procedures herein were utilized to prepare(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-aceticacid. HRMS (ES⁺) m/z exact mass calcd for C₂₄H₃ LN₂O₄ [M+1] 411.2284,found 411.2269. ¹H NMR.

Example 1703-(4-{2-[-(4-Methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid

The procedures herein were utilized to prepare3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₅H₃₃N₂O₄ [M+1] 425.2440,found 425.2427. ¹H NMR.

Example 1713-{2-[1-(4-Methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-benzoicacid

The procedures herein were utilized to prepare3-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy]-benzoicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₃H₂₉N₂O₄ [M+1] 397.2127,found 397.2118. ¹H NMR.

Example 172 Step A 1-(4-Hydroxy-phenyl)-cyclopentanecarboxylic acidethyl ester

A solution of 1-(p-methoxyphenyl)-cyclopentanecarboxylic acid 093909(5.0 g, 22.7 mmol) in ethanol (50 mL) was treated with conc. H₂SO₄ (4.40g, 44.9 mmol) and heated to reflux under N₂ for 12 h. The reaction wascooled and the solvent removed in vacuo to give a residue that wasextracted with EtOAc and water. The organic layer was dried (MgSO₄) andthe solvent removed in vacuo to 5.93 g crude ester (100%) that wasutilized without purification. The ester (5.93 g, assume 22.7 mmol) wasdissolved in dry CH₂Cl₂ (75 mL), cooled to −78° C. and then treateddropwise with BBr₃ (11.4 g, 45.6 mmol). The reaction was warmed to 0° C.for 15 minutes and then quenched with methanol then water. The reactionmixture was extracted with CH₂Cl₂ and water, the organic layer was dried(MgSO₄), and the solvent removed in vacuo to give crude product that waspurified by flash chromatography using 6:1 hexanes:EtOAc to afford 4.34g (79%) 1-(4-hydroxy-phenyl)-cyclopentanecarboxylic acid ethyl ester. MS(ES⁺) Calc'd for C₁₄H₁₉O₃ (M+1) 235. Found m/z 235 (100%). ¹H NMR.

Step B1-(4-{2-[1-(4-Methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-cyclopentanecarboxylicacid

A mixture of 1-(4-hydroxy-phenyl)- cyclopentanecarboxylic acid ethylester (0.042 g, 0.179 mmol), toluene-4-sulfonic acid2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethyl ester(0.085 g, 0.197 mmol) and 325 mesh K₂CO₃ (0.050 g, 0.362 mmol) inethanol (5 mL) was heated at ref lux for under N₂ for 16 h. The reactionwas then treated with aqueous 5 N NaOH (0.5 mL) and heated to reflux 1.5h. The reaction mixture was cooled, the solvent removed in vacuo. Theresultant residue was acidified with aqueous 1 N HCl (10 mL) andextracted with Et₂O. The organic layer was dried (MgSO₄) and the solventremoved in vacuo to afford 0.058 g crude acid that was purified bypreparative HPLC to afford 0.033 g (40%)1-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-cyclopentanecarboxylicacid. MS (ES⁺) Calc'd for C₂₈H₃₇N₂O₄ (M+1) 465. Found m/z 465 (100%). ¹HNMR.

Example 173 2-Methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-3-phenyl-propionic acid

The procedures herein were utilized to prepare2-methyl-2-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenoxy)-3-phenyl-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₃₂H₃ BN₂O₅ [M+1] 531.2859,found 531.2855. ¹H NMR.

Example 174 2-Methoxy-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The procedures herein were utilized to prepare2-Methoxy-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid. MS (ES⁺) Calc'd for C₂₆H₃₅N₂O₅ (M+1) 455. Found m/z 455 (100%). ¹HNMR.

Example 175 Step A 5-[3-(4-Methoxy-phenyl)-propyl]-3-(4-methyl-benzyl)-imidazolidine-2,4-dione

A solution of 5-[3-(4-methoxy-phenyl)-propyl]-imidazolidine-2,4-dione(2.00 g, 8.05 mmol) in DMF (80 mL) was treated with p-methyl benzylbromide (1.64 g, 8.86 mmol), MgSO₄ (1.94 g, 16.1 mmol) and then 325 meshK₂CO₃ (2.12 g, 15.3 mmol). The resultant mixture was stirred under N₂ inan ice bath for 30 minutes and then warmed to room temperature for 16 h.The reaction mixture was then filtered, and then aqueous 1N HCl (40 mL)was added to the filtrate. The filtrate was extracted with EtOAc and theorganic layer dried (MgSO₄). The solvent was removed in vacuo to give acrude product which was purified by flash chromatography using 3:1hexanes:EtOAc to afford 2.41 g (85%)5-[3-(4-methoxy-phenyl)-propyl]-imidazolidine-2,4-dione. MS (ES⁺) Calc'dfor C₂₁H₂₅N₂O₃ (M+1) 353. Found m/z 353 (100%). ¹H NMR.

Step B5-[3-(4-Methoxy-phenyl)-propyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione

A 0° C. solution of compound5-[3-(4-methoxy-phenyl)-propyl]-imidazolidine-2,4-dione (2.41 g, 6.84mmol) in DMF (35 mL) was treated with sodium hydride (60% dispersion,0.23 g, 5.75 mmol) and warmed to room temperature and stirred under N₂for 15 minutes. The resultant mixture was cooled to 0° C. and thentreated with 1-propyl iodide (0.96 g, 5.64 mmol) and then warmed to roomtemperature and stirred for 1 h. The reaction was quenched with 1 N HCl(20 mL) and then worked up extractively with Et₂O and water. The organiclayer was dried (MgSO₄) and the solvent removed in vacuo to give crudeproduct that was purified by flash chromatography using a 6:1hexanes:EtOAc to afford 1.58 g (71%)5-[3-(4-methoxy-phenyl)-propyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione. MS (ES⁺) Calc'd for C₂₄H₃₁N₂O₃ (M +1) 395.Found m/z 395 (100%). ¹H NMR.

Step C4-[3-(4-Methoxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one

A solution of 5-[3-(4-methoxy-phenyl)-propyl]-3-(4-methyl-benzyl)-1-propyl-imidazolidine-2,4-dione (1.26 g, 3.19 mmol) in THF (20ml) was treated dropwise with 1 M solution of borane-THF complex in THF(16 mL, 16 mmol) and then stirred at room temperature under N₂ for 22 h.The reaction was quenched with methanol (20 mL) and stirred at roomtemperature for 2 hr. The solvent was removed in vacuo to give 1.25 g(100%) crude4-[3-(4-methoxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-onethat was carried on without purification. MS (ES⁺) Calc'd for C₂₄H₃₃N₂O₂(M+1) 381. Found m/z 381 (100%). ¹H NMR.

Step D4-[3-(4-Hydroxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one

A solution of 4-[3-(4-methoxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one (1.22 g, assume 3.21 mmol) wasdissolved in dry CH₂Cl₂ (25 mL), cooled to 0° C. and then treateddropwise with BBr₃ (2.41 g, 9.63 mmol). The reaction was stirred at 0°C. for 1 h. The reaction mixture was diluted with Et₂O and water, theorganic layer was dried (MgSO₄), and the solvent removed in vacuo togive crude product that was purified by flash chromatography using 1:1hexanes:EtOAc to afford 0.687 g (68%) 4-[3-(4-hydroxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one. MS(ES⁺) Calc'd for C₂₃H₃₁N₂O₂ (M+1) 367. Found m/z 367 (100%). ¹H NMR.

Step E 2-Methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionic acid ethyl ester

A mixture of 4-[3-(4-hydroxy-phenyl)-propyl]-1-(4-methyl-benzyl)-3-propyl-imidazolidin-2-one (0.687 g, 1.87 mmol), ethyl2-bromoisobutyrate (2.55 g, 13.1 mmol), MgSO₄ (0.22 g, 1.83 mmol) and325 mesh K₂CO₃ (0.77 g, 5.57 mmol) in ethanol (60 mL) was heated at 70°C. for under N₂ for 16 h. The reaction mixture was cooled and thesolvent removed in vacuo to give a residue that was acidified with 1 NHCl (20 mL). The reaction was diluted with EtOAc and washed with water.The organic layer was dried (MgSO₄) and the solvent removed in vacuo togive crude product that was purified by flash chromatography using 5:1hexanes:acetone to afford 0.648 g (72%)2-methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionic acid ethyl ester. MS (ES⁺)Calc'd for C₂₉H₄₁N₂O₄ (M+1) 481. Found m/z 481 (100%). ¹H NMR.

Step F 2-Methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionic acid

A solution of2-methyl-2-(4-{3-[(1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionicacid ethyl ester (0.191 g, 0.397 mmol) in ethanol (10 mL) was treatedwith aqueous 5 N NaOH (0.8 mL) and heated to reflux 1.5 h. The reactionmixture was cooled, the solvent removed in vacuo. The resultant residuewas acidified with aqueous 1 N HCl (10 mL) and extracted with Et₂O. Theorganic layer was dried (MgSO₄) and the solvent removed in vacuo toafford 0.178 g (99%)2-methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₇N₂O₄ [M+1] 453.2753,found 453.2751. ¹H NMR.

Example 176 (R)-2-Methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionic acid

The procedures herein were utilized to prepare(R)-2-methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-propionicacid. HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₇N₂O₄ [M+1] 453.2753,found 453.2757. ¹H NMR.

Example 177 Step A2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid tert-butyl ester

Compound2-{4-[3-(2,5-dioxo-imidazolidin-4-yl)-propyl]-phenoxy}-2-methyl-propionicacid tert-butyl ester (0.29 g, 0.770 mmol) in DMF (10 mL) was treatedwith 3,4-dimethyl benzyl chloride (0.131 g, 0.847 mmol), MgSO₄ (0.185 g,1.54 mmol) and then 325 mesh K₂CO₃ (0.213 g, 1.54 mmol). The resultantmixture was heated to 50° C. under N₂ for 4 h. The reaction mixture wascooled and quenched with 1N HCl (8 mL) and then extracted with EtOAc andwater. The organic layer was dried (MgSO₄) and the solvent was removedin vacuo to give a crude product which was purified by flashchromatography using a gradient of 4:1 then 1:1 hexanes:EtOAc to afford0.202 g (53%)2-(4-{3-[1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid tert-butyl ester. MS (ES⁺) Calc'd for C₂₉H₃₉N₂O₅ (M+1) 495. Foundm/z 495 (100%). ¹H NMR.

Step B2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid tert-butyl ester

A solution of2-(4-{3-[1-(3,4-dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid tert-butyl ester (0.113 g, 0.228 mmol) in THF (6 mL) was treateddropwise with 1 M solution of borane-THF complex in THF (4.4 mL, 4.4mmol) and then stirred at room temperature under N₂ for 32 h. Thereaction was quenched with methanol (6 mL) and stirred at roomtemperature for 2 hr. The solvent was removed in vacuo to give crudeproduct that was purified by flash chromatography using 97:3 CH₂Cl₂:MeOHto afford 0.051 g (47%)2-(4-{3-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid tert-butyl ester. MS (ES⁺) Calc'd for C₂₉H₄₁N₂O₄ (M+1) 481. Foundm/z 481 (100%). ¹H NMR.

Step C2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid

A solution of2-(4-{3-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid tert-butyl ester (0.051 g, 0.106 mmol) in CH₂Cl₂ (3 mL) was treatedwith trifluoroacetic acid (0.5 mL) and stirred at room temperature underN₂ for 5 h. The solvent removed in vacuo to give crude acid that waspurified by flash chromatography using 94:6 CH₂Cl₂:MeOH to afford 0.011g (24%)2-(4-{3-[1-(3,4-dimethyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl]-phenoxy}-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₅H₃₃N₂O₄ (M+1) 425. Found m/z 425 (100%). ¹HNMR.

Example 1782-(4-{3-[1-(4-tert-Butyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid

The procedures herein were utilized to prepare2-(4-{3-[1(4-tert-butyl-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₇H₃₇N₂O₄ (M+1) 453. Found m/z 453 (100%). ¹HNMR.

Example 1792-(4-{3-[1-(4-Chloro-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid

The procedures herein were utilized to prepare2-(4-{3-[1-(4-chloro-benzyl)-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₃H₂₈ClN₂O₄ (M+1) 431. Found m/z 431 (100%).

Example 1802-(4-{3-[1-(4-Chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid

The procedures herein were utilized to prepare2-(4-{3-[1-(4-chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₄H₃₀ClN₂O₄ (M+1) 445. Found m/z 445 (100%).

Example 1812-Methyl-2-{4-[3-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid

The procedures herein were utilized to prepare2-methyl-2-{4-[3-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid. MS (ES⁺) Calc'd for C₂₈H₃₃N₂O₄ (M+1) 461. Found m/z 461 (100%).

Example 1822-{4-[3-(3-Ethyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-2-methyl-propionicacid

The procedures herein were utilized to prepare2-{4-[3-(3-ethyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-2-methyl-propionicacid. MS (ES⁺) Calc'd for C₂₉H₃₅N₂O₄ (M+1) 475. Found m/z 475 (100%).

Example 1832-Methyl-2-{4-[3-(1-naphthalen-2-ylmethyl-2-oxo-3-propyl-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid

The procedures herein were utilized to prepare2-methyl-2-{4-[3-(1-naphthalen-2-ylmethyl-2-oxo-3-propyl-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid. MS (ES⁺) Calc'd for C₃₀H₃₇N₂O₄ (M+1) 489. Found m/z 489 (100%).

Example 1842-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-ethyl-butyricacid

A mixture of 1-(4-tert-butyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.077 g, 0.202 mmol),potassium tert-butoxide (0.091 g, 0.745 mmol) and ethylα-bromodiethylacetate (0.361 g, 1.61 mmol) in 2-methyl-2-propanol (8 mL)was heated to 100° C. under N₂ for 16 h. Aqueous 5 N NaOH (1.5 mL) wasadded to the reaction mixture and it was heated at reflux an additional1 h. The reaction mixture was cooled and quenched with 1 N HCl. Themixture was then diluted with water and extracted with CH₂Cl₂. Theorganic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.288 g of crude product that was purified by preparative HPLC togive 0.014 g (14%)2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-ethyl-butyricacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calcd for C₃₀H₄₃N₂O₄ [M+1]495.3223, found 495.3252.

Example 185 1-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-cyclohexanecarboxylic acid

A mixture of 1-(4-tert-butyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-imidazolidin-2-one (0.074 g, 0.194 mmol) andpotassium tert-butoxide (0.044 g, 0.392 nmol) in 2-methyl-2-propanol (8mL) was heated to 60° C. under N₂ and then and methyl1-bromocyclohexanecarboxylate (0.274 g, 1.16 mmol) was added dropwise tothe to 600 C solution. Additional potassium tert-butoxide (0.044 g,0.392 mmol) and methyl 1-bromocyclohexanecarboxylate (0.274 g, 1.16mmol) was added to the reaction and it was stirred for 2 h. The reactionmixture was cooled and quenched with 1 N HCl. The mixture was thendiluted with water and extracted with CH₂Cl₂. The organic layer wasdried (Na₂SO₄) and the solvent removed in vacuo to afford 0.400 g ofcrude product that was purified by preparative HPLC to give 0.059 g(60%)1-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-cyclohexanecarboxylicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calcd for C₃₁H₄₃N₂O₄ [M+1]507.3223, found 507.3237.

Example 186 2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-ethyl-hexanoic acid

The procedures herein were utilized to prepare2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-ethyl-hexanoicacid ¹H NMR. HRMS (ES⁺) m/z exact mass calcd for C₃₂H₄₇N₂O₄ [M+1]523.3536, found 523.3555.

Example 187 2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid

The procedures herein were utilized to prepare2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calcd for C₂₉H₄₂N₂O₄ [M+1]481.3066, found 481.3062.

Example 188 2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-4-methyl-pentanoic acid

The procedures herein were utilized to prepare2-(4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-4-methyl-pentanoicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calcd for C₃₀H₄₃N₂O₄ [M+1]495.3223, found 495.3244.

Example 189 Step A 2-bromo-2-methyl-pentanoic acid

A mixture of 2-methylpentoic acid (10.0 g, 86.1 mmol), N-bromosuccinimide (22.98 g, 129 mmol) and conc. H₂SO₄ (2.5 mL) intrifluoroacetic acid (50 mL) was heated to reflux under N₂ for 16 h. Thereaction was cooled and the solvent removed in vacuo and the crude oilwas purified via vacuum distillation (1 mm, 135-140° C.) to give aslowly crystallizing oil that was diluted with CH₂Cl₂ and then filteredto remove solids. The solvent was removed in vacuo to afford 9.08 g(54%) of 2-bromo-2-methyl-pentanoic acid. ¹H NMR.

Step B4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one

A solution of4-[3-(4-methoxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one(3.51 g, 8.63 mmol) in dry CH₂Cl₂ (60 mL), cooled to −78° C. and thentreated dropwise with BBr₃ (6.49 g, 25.9 mmol). The reaction was warmed0° C. and stirred for 2 h under N₂. The reaction mixture was dilutedwith water and extracted with CH₂Cl₂. The organic layer was dried(MgSO₄), and the solvent removed in vacuo to give crude product that waspurified by flash chromatography using 2:1 hexanes:acetone to afford3.01 g (89%)4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one.¹H NMR. MS (ES³⁰) Calc'd for C₂₁H₂₄N₂O₂F₃ (M+1) 393. Found m/z 393(100%).

Step C 2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid ethyl ester

A mixture of4-[3-(4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one(0.51 g, 1.30 mmol) and 2-bromo-2-methyl-pentanoic acid (2.54 g, 13.0mmol) in 2-methyl-2-propanol (10 mL) was heated to 45° C. under N₂ andthen a solution of 1 M potassium tert-butoxide in 2-methyl-2-propanol(27.3 mL, 27.3 mmol) was added dropwise and the reaction was stirred at45° C. for 40 minutes. The reaction mixture was cooled and quenched with1 N HCl (50 mL). The mixture was then diluted with water and extractedwith Et₂O. The organic layer was dried (Na₂SO₄) and the solvent removedin vacuo to afford crude product that was combined with EtOH (50 mL) andconc. H₂SO₄ (6 mL). The mixture was heated to reflux for 3 h. Thereaction mixture was cooled and the solvent removed in vacuo. Theresidue was diluted with water and extracted with EtOAc and the organiclayer was dried (Na₂SO₄). The solvent was removed in vacuo to give crudeproduct that was purified by flash chromatography using 5:1hexanes:acetone to afford 0.491 g (71%)2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl)-propyl}-phenoxy)-pentanoicacid ethyl ester. This material could be purified by chiral preparativeHPLC (conditions,) ¹H NMR. MS (ES⁺) m/z calcd for C₂₉H₃₈N₂O₄F₃ [M+1]535. Found 535 (100%).

Step D 2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid

A mixture of2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoic acid ethyl ester (0.020 g, 0.040 mmol) and 5 N NaOH (0.5 mL)in EtOH (6 mL) was heated at reflux for 1 h. The reaction mixture wascooled and quenched with 1 N HCl. The mixture was then diluted withwater and extracted with CH₂Cl₂. The organic layer was dried (Na₂SO₄)and the solvent removed in vacuo to afford 0.010 g (53%)2-methyl-2-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-pentanoicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calcd for C₂₇H₃₄N₂O₄F₃ [M+1]507.2471, found 507.2459.

Example 190 Step A2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester

A mixture of 3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester0.027 g, 0.120 mmol), toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethylester (0.061 g, 0.133 mmol) and Cs₂CO₃ (0.059 g, 0.181 mmol) in DMF (4mL) was heated to 55° C. under N₂ for 16 h. The reaction was cooled andquenched with 1 N HCl (10 mL) and worked up extractively with Et₂O andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford crude product that was purified by flash chromatographyusing 4:1 then 3:1 hexanes:acetone to afford 0.040 g (64%)2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester. ¹H NMR. MS (ES⁺) Calc'd for C₂₆H₃₂N₂O₅F₃(M+1) 509. Found m/z 509 (100%).

Step B 2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester (0.040 g, 0.079 mmol) in ethanol (5 mL) wastreated with aqueous 5 N NaOH (0.5 mL) and stirred at room temperaturefor 2 h. The solvent removed in vacuo. The resultant residue wasacidified with aqueous 1 N HCl (10 mL) and extracted with CH₂Cl₂. Theorganic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.026 g (68%)2-methoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid. ¹H NMR. MS (ES⁺) m/z calc'd for C₂₄H₂₈N₂O₅F₃ (M+1) 481.Found m/z 481.

Example 191 2-ethoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

The procedures herein were utilized to prepare2-ethoxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid. ¹H NMR. MS (ES⁺) m/zcalc'd for C₂₅H₃₀N₂O₅F₃ (M+1) 495. Found m/z 495.

Example 192 3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-propoxy-propionic acid

The procedures herein were utilized to prepare3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-propoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₂₆H₃₂N₂O₅F₃ (M+I)509.2263. Found m/z 509.2268.

Example 193 Step A 3-(4-benzyloxy-phenyl)-2-cyclopentyloxy-propionicacid cyclopentyl ester

A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (1.0 g,3.67 mmol), cyclopentyl iodide (7.2 g, 36.7 mmol) and silver (I) oxide(4.25 g, 18.3 mmol) in DMF (15 mL) was heated at 55° C. under N₂ for 72h. The reaction mixture was cooled, diluted with Et₂O and filteredthrough hyflo. The filtrate was extracted with water and the organiclayer was dried (MgSO₄) and the solvent removed in vacuo to afford crudeproduct that was purified by flash chromatography using 10:1hexanes:acetone to afford 0.255 g (17%)3-(4-benzyloxy-phenyl)-2-cyclopentyloxy-propionic acid cyclopentylester. R_(f) 0.67 (1:1 hexanes:acetone). ¹H NMR.

Step B 2-cyclopentyloxy-3-(4-hydroxy-phenyl)-propionic acid cyclopentylester

A mixture of 3-(4-benzyloxy-phenyl)-2-cyclopentyloxy- propionic acidcyclopentyl ester (0.137 g, 0.335 mmol) and 10% Pd/C (0.14 g) in EtOAc(70 mL) was purged with N₂ then H₂ and then stirred under a H₂ balloonatmosphere for 3 h at room temperature. Upon reaction completion, MgSO₄was added and the mixture filtered through hyflo. The solvent wasremoved in vacuo to afford 0.090 g (84%)2-cyclopentyloxy-3-(4-hydroxy-phenyl)-propionic acid cyclopentyl ester.¹H NMR. MS (ES⁻) Calc'd for C₁₉H₂₅O₄ (M−1) 317. Found m/z 317 (100%).

Step C2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid cyclopentyl ester

A mixture of 2-cyclopentyloxy-3-(4-hydroxy-phenyl)-propionic acidcyclopentyl ester(0.090 g, 0.283 mmol), toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl- benzyl)-imidazolidin-4-yl]-ethylester (0.140 g, 0.307 mmol) and Cs₂CO₃ (0.138 g, 0.423 mmol) in DMF (10mL) was heated to 65° C. under N₂ for 16 h. The reaction was cooled andquenched with 1 N HCl (10 mL) and worked up extractively with Et₂O andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford crude product that was purified by flash chromatographyusing 3:1 hexanes:acetone to afford 0.108 g (64%)2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid cyclopentyl ester. ¹HNMR. MS (ES⁺) Calc'd for C₃₃H₄₂N₂O₅F₃ (M+1) 603. Found m/z 603 (100%).

Step D2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid

A solution of2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid cyclopentyl ester (0.108 g, 0.179 mmol) in ethanol (10mL) was treated with aqueous 5 N NaOH (1 mL) and stirred at roomtemperature for 3 h. The solvent removed in vacuo. The resultant residuewas acidified with aqueous 1 N HCl (10 mL) and extracted with CH₂Cl₂.The organic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.106 g of crude acid that was purified by chiral HPLC (20×250 nmChiralpak AD, 3:2 heptane:IPA with 0.1% trifluoroacetic acid mobilephase, 14 mL/min, 225 nm) to give 0.080 g (83%) of 100% de2-cyclopentyloxy-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₂₈H₃₄N₂O₅F₃ (M+1)535.2420. Found m/z 535.2408.

Example 194 Step A5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one

A mixture of 3-(4-benzyloxy-phenyl)-2-hydroxy-propionic acid (2.0 g,7.34 mmol), 2,2-dimethoxypropane (18.63 g, 179 mmol) and pyridiniump-toluene sulfonate (0.92 g, 3.66 mmol) in CHCl₃ (80 mL) was heated toreflux for 40 minutes under N₂. The reaction was cooled and worked upextractively with CH₂Cl₂ and water. The organic layer was dried (Na₂SO₄)and the solvent removed in vacuo to afford crude product that waspurified by flash chromatography using 10:1 hexanes:acetone to afford2.01 g (88%) 5-(4-benzyloxy- benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one.R_(f)=0.53 (1:1 hexanes:acetone). ¹H NMR (500 MHz, CDCl₃) δ 7.43-7.35(m, 4H), 7.34-7.29 (m, 1H), 7.16 (d, 2H, J=8.80 Hz), 6.91 (d, 2H, J=8.80Hz), 5.04 (s, 2H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.13 (dd, 1H,J=14.67 Hz, J=4.40 Hz), 2.99 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 1.50 (s,3H), 1.36 (s, 3H); MS (ES⁺) Calc'd for C₁₉H₂₀O₄ (M+NH4) 330. Found m/z330 (100%).

Step B 5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one

A mixture of 5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one(1.0 g, 3.20 mmol) and 10% Pd/C (0.75 g) in EtOAc (40 mL) was purgedwith N₂ then H₂ and then stirred under a H₂ balloon atmosphere for 3 hat room temperature. Upon reaction completion, Na₂SO₄ was added and themixture filtered through hyflo. The solvent was removed in vacuo toafford 0.747 g (100%)5-(4-hydroxy-benzyl)-2,2-dimethyl-(1,3]dioxolan-4-one. ¹H NMR (500 MHz,CDCl₃) δ 7.11 (d, 2H, J=8.31 Hz), 6.76 (d, 2H, J=8.31 Hz), 4.92 (bs,1H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.11 (dd, 1H, J=14.67 Hz,J=4.40 Hz), 2.98 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 1.50 (s, 3H), 1.36 (s,3H); MS (ES⁻) Calcld for C₁₂H₁₃O₄ (M−1) 221. Found m/z 221 (100%).

Step C 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester

A 0° C. solution of5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (0.20 g, 0.900mmol) and triethylsilane (1.05 g, 9.0 mmol) in dry CH₂Cl₂ (10 mL) wastreated dropwise with a 1 molar solution of TiCl₄ in CH₂Cl₂ (0.90 mL,0.900 mmol) under N₂. The resultant red slurry was stirred at 0° C. for15 minutes and then warmed to room temperature for 45 minutes. Thereaction mixture was quenched with water and extracted with EtOAc. Theorganic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.320 g of crude acid that was carried on as is. The oil wasdissolved in EtOH (25 mL) and treated with conc. H₂SO₄ (1 mL) and thenstirred at room temperature for 17 h under N₂. The solvent was removedin vacuo and the oil extracted with EtOAc and water. The organic layerwas dried (Na₂SO₄) and the solvent removed in vacuo to afford crudeproduct that was purified by flash chromatography using 5:1hexanes:acetone to give 0.158 g (70%)3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester. R_(f)=0.48(1:1 hexanes:acetone). ¹H NMR (500 MHz, CDCl₃) δ 7.10 (d, 2H, J=8.80Hz), 6.73 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H) 4.20-4.12 (m, 2H), 3.99 (dd,1H, J=8.31 Hz, J=4.89 Hz), 3.49 (hp, 1H, J=5.87 Hz), 2.95-2.83 (m, 2H),1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=6.36 Hz), 0.97 (d, 3H, J=6.36Hz); MS (ES⁻) Calc'd for C₁₄H₁₉O₄ (M−1) 251. Found m/z 251 (100%). 97.6%ee by chiral HPLC assay (Chiralcel OJ, 4.6×250 mm, 90/10 heptane/IPAeluent, 1 mL/min, 266 nm).

Step D3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionicacid ethyl ester

A mixture of 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethylester (0.034 g, 0.134 mmol), toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)- imidazolidin-4-yl]-ethylester (0.068 g, 0.149 mmol) and CS₂CO₃ (0.066 g, 0.202 mmol) in DMF (6mL) was heated to 65° C. under N₂ for 16 h. The reaction was cooled andquenched with 1 N HCl (10 mL) and worked up extractively with Et₂O andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford crude product that was purified by flash chromatographyusing 4:1 hexanes:acetone to afford 0.048 g (67%)3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionicacid ethyl ester. R_(f)=0.36 (1:1 hexanes:acetone). ¹H NMR (500 MHz,CDCl₃)δ ¹H NMR (500 MHz, CDCl₃)□ 7.56 (d, 2H, J=8.07 Hz), 7.36 (d, 2H,J=8.07 Hz), 7.13 (d, 2H, J=8.80 Hz), 6.72 (d, 2H, J=8.80 Hz), 4.47, 4.36(AB_(q), 2H, J=15.16 Hz), 4.20-4.12 (m, 2H), 4.00-3.94 (m, 3H),3.66-3.59 (m, 1H), 3.48 (hp, 1H, J=5.87 Hz), 3.37 (t, 1H, J=8.80 Hz),2.98 (t, 1H, J=8.80 Hz), 2.90- 2.85 (m, 2H), 2.84 (s, 3H), 2.27-2.23 (m,1H), 1.93-1.84 (m, 1H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=5.87Hz), 0.97 (d, 3H, J=5.87 Hz). MS (ES⁺) Calc'd for C₂₈H₃₆N₂O₅F₃ (M+1)537. Found m/z 537 (100%).

Step E3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionicacid

A solution of3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid ethyl ester (0.048 g, 0.089 mmol) in ethanol (8 mL) wastreated with aqueous 5 N NaOH (1.5 mL) and stirred at room temperaturefor 2 h. The solvent removed in vacuo. The resultant residue wasacidified with aqueous 1 N HCl (15 mL) and extracted with CH₂Cl₂. Theorganic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.038 g (84%)3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-isopropoxy-propionic acid. ¹H NMR (500 MHz, CDCl₃) δ 7.49 (d, 2H, J=8.07 Hz), 7.30(d, 2H, J=8.07 Hz), 7.06 (d, 2H, J=8.31 Hz), 6.66 (d, 2H, J=8.31 Hz),4.40, 4.31 (AB_(q), 2H, J=15.65 Hz), 4.03-4.01 (m, 1H), 3.90 (t, 2H,J=5.87 Hz), 3.59-3.53 (m, 1H), 3.48 (hp, 1H, J=5.87 Hz), 3.31 (t, 1H,J=8.80 Hz), 3.12-2.96 (m, 1H), 2.95 (t, 1H, J=8.80 Hz), 2.90-2.79 (m,1H), 2.78 (s, 3H), 2.27-2.23 (m, 1H), 1.93-1.84 (m, 1H), 1.14 (d, 3H,J=5.87 Hz), 0.97 (d, 3H, J=5.87 Hz). HRMS (ES⁺) m/z exact mass calc'dfor C₂₆H₃₂N₂O₅F₃ (M+1) 509.2274. Found m/z 509.2263.

Example 1952-(1-ethyl-propoxy)-3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid

The procedures herein were utilized to prepare 2-(1-ethyl-propoxy)-3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid. ¹H NMR. MS (ES⁺) m/zcalc'd for C₂₈H₃₅N₂O₅F₃ (M+1) 537. Found m/z 537.

Example 196 2-methoxy-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-propionic acid

The procedures herein were utilized to prepare2-methoxy-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-propionic acid. ¹H NMR. HRMS (ES⁺)m/z exact mass calc'd for C₂₅H₃₀N₂O₄F₃ (M+1) 479.2158. Found m/z479.2171.

Example 1972-methoxy-2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-propionic acid

The procedures herein were utilized to prepare2-methoxy-2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-propionic acid. ¹H NMR. HRMS (ES⁺)m/z exact mass calc'd for C₂₆H₃₂N₂O₄F₃ (M+1) 493.2314. Found m/z493.2321.

Example 198 Step A 2-(4-trifluoromethyl-phenoxy)-propionic acid ethylester

A mixture of trifluromethyl-p-cresol (9.74 g, 60.1 mmol), ethyl2-bromopropionate (10.9 g, 60.1 mmol) and Cs₂CO₃ (39.15 g, 120 mmol) inDMF (450 mL) was heated at 90° C. under N₂ for 16 h. The reaction wascooled and filtered using Et₂O to rinse the solids. The filtrate waswashed with 1 N HCl (200 mL) and water. The organic layer was dried(Na₂SO₄) and the solvent removed in vacuo to afford 19.03 g of crudeproduct that was purified by flash chromatography using 6:1hexanes:acetone to afford 13.96 g (89%)2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester. R_(f)=0.63(1:1 hexanes:acetone). 1 NMR.

Step B3-(3-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester

A −78° C. solution of 2-(4-trifluoromethyl-phenoxy)-propionic acid ethylester (10.0 g, 38.1 mmol) in THF (80 mL) was transferred via cannula toa −78° C. solution of 1.5 M LDA- THF complex (45.8 mL, 68.7 mmol) in THF(80 mL). The resultant mixture was stirred for 5 minutes at −78° C. andthen 3-benzyloxybenzaldehyde (7.3 g, 34.4 mmol) was added in one portionand the reaction mixture stirred at −78° C. for 5 minutes and was thenwas quenched with a −78° C. THF solution of acetic acid (6.82 g, 113.5mmol). The reaction mixture was diluted with aqueous saturated NH₄Cl andextracted with Et₂O. The organic layer was dried (Na₂SO₄) and thesolvent removed in vacuo to afford 19.84 g of crude product that waspurified by flash chromatography using 8:1 then 4:1 hexanes:acetone toafford 7.88 g (44%) 3-(3-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(4-trifluoromethyl-phenoxy)- propionic acidethyl ester as a mixture of diasteriomers. R_(f)=0.55 (1:1hexanes:acetone). 1 NMR.

Step C 3-(3-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester

Trifluoroacetic anhydride (6.99 g, 33.3 mmol) was added dropwise to a 0°C. solution of3-(3-benzyloxy-phenyl)-3-hydroxy-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester (7.88 g, 16.6 mmol) and pyridine (13.10 g, 0.166 mol)in CH₂Cl₂ (150 mL). The reaction solution was warmed to room temperatureand stirred under N₂ for 3 h. The reaction solution was washed twicewith aqueous 1 N HCl (175 mL each) and the organic layer dried (MgSO₄).The solvent was removed in vacuo to give 9.03 g (95%) of crude3-(3-benzyloxy-phenyl)-2-methyl-3-(2,2,2-trifluoro-acetoxy)-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester which was carried on immediately.

The 3-(3-benzyloxy-phenyl)-2-methyl-3-(2,2,2-trifluoro-acetoxy)-2-(4-trifluoromethyl-phenoxy)-propionic acid ethyl ester (9.03g, 15.8 mmol) was combined with 10% Pd/C (9.0 g) in ethyl acetate (200mL). The mixture was purged with N₂ then H₂ and then stirred at roomtemperature under a H₂ balloon for approximately 48 h. The reactionmixture was filtered through hyflo to remove the catalyst and theresultant filtrate dried (MgSO₄). The solvent was removed in vacuo togive crude product that was purified by flash chromatography using 3:1hexanes:acetone to afford 1.96 g (32%)3-(3-hydroxy-phenyl)-2-methyl-2-(4-trifluoromethyl- phenoxy)-propionicacid ethyl ester. The racemic phenol was purified by preparative chiralHPLC (Chiralcel OD, 5×37 cm, 95:5 heptane:IPA mobile phase, 150 ml/min,285 nm, GK8-A015150-031). R_(f)=0.32 (1:1 hexanes:acetone). 1 NMR. MS(ES⁻) Calc'd for C₁₉H₁₈O₄F₃ (M−1) 367. Found m/z 367 (100%).

Step D 2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester

A mixture of 3-(3-hydroxy-phenyl)-2-methyl-2-phenoxy- propionic acidethyl ester (0.100 g, 0.271 mmol), toluene-4-sulfonic acid2-[3-methyl-2-oxo-1-(4-trifluoromethyl- benzyl)-imidazolidin-4-yl]-ethylester (0.136 g, 0.298 mmol) and Cs₂CO₃ (0.133 g, 0.408 mmol) in DMF (8mL) was heated to 65° C. under N₂ for 17 h. The reaction was cooled andquenched with 1 N HCl (10 mL) and worked up extractively with Et₂O andwater. The organic layer was dried (MgSO₄) and the solvent removed invacuo to afford crude product that was purified by flash chromatographyusing 4:1 hexanes:acetone to afford 0.113 g (64%)2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester. ¹H NMR. MS (ES⁺) Calc'd for C₃₃H₃₅N₂O₅F₆ (M +1) 653.Found m/z 653 (100%).

Step E 2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid

A solution of2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid ethyl ester (0.113 g, 0.173 mmol) in ethanol (12 mL) was treatedwith aqueous 5 N NaOH (2 mL) and heated to reflux 1 h. The reactionmixture was cooled, the solvent removed in vacuo. The resultant residuewas acidified with aqueous 1 N HCl (15 mL) and extracted with CH₂Cl₂.The organic layer was dried (Na₂SO₄) and the solvent removed in vacuo toafford 0.108 g (100%)2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-trifluoromethyl-phenoxy)-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₁H₃₁N₂O₅F₆ (M+1)625.2137. Found m/z 625.2134.

Example 199 2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionic acid

The procedures herein were utilized to prepare2-methyl-3-(3-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(3-trifluoromethyl-phenoxy)-propionic acid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd forC₃₁H₃₁N₂O₅F₆ (M+1) 625.2137. Found m/z 625.2128.

Example 2003-{4-[2-(1-hexyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid

The procedures herein were utilized to prepare3-{4-[2-(1-hexyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₂₈H₃₉N₂O₅ (M+1)483.2859. Found m/z 483.2882.

Example 201 3-{4-[2-(1-benzo[1,3]dioxol-5-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy- propionic acid

The procedures herein were utilized to prepare3-{4-[2-(1-benzo[1,3]dioxol-5-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy)-phenyl}-2-methyl-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₀H₃₃N₂O₇ (M+1)533.2288. Found m/z 533.2305.

Example 202 2-methyl-3-{4-[2-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid

The procedures herein were utilized to prepare2-methyl-3-{4-[2-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₂H₃₄N₃O₅ (M+1)540.2498. Found m/z 540.2523.

Example 203 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy- propionic acid

The procedures herein were utilized to prepare2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester.¹H NMR. MS (ES⁺) m/z calc'd for C₃₀H₃₂N₂O₆F₃ (M +1) 573. Found m/z 573.

Example 204 2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy- propionic acid

The procedures herein were utilized to prepare2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-p-tolyloxy-propionic acid. ¹H NMR.HRMS (ES⁺) m/z exact mass calc'd for C₃₁H₃₄N₂O₅F₃ (M+1) 571.2420. Foundm/z 571.2423.

Example 2052-(benzo[1,3]dioxol-5-yloxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-(4-trifluororoethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid

The procedures herein were utilized to prepare 2-(benzo[1,3)dioxol-5-yloxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd for C₃₁H₃₂N₂O₇F₃ (M+1)601.2162. Found m/z 601.2180.

Example 2063-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid

The procedures herein were utilized to prepare3-(4-{2-[1-(4-hydroxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionic acid. ¹H NMR. HRMS (ES⁺) m/z exact mass calc'd forC₃₁H₃₁N₂O₅F₆ (M+1) 625.2137. Found m/z 625.2144.

Example 207 3-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy- propionic acid

The procedures herein were utilized to prepare3-(4-{2-[1-(3,4-dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid. ¹H NMR. HRMS (ES⁺) m/z exact mass calcld for C₃₁H₃₇N₂O₅ (M+1)517.2702. Found m/z 517.2704.

Example 208 2-(2-Butyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid

Step A 2-(2-Butyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionicacid methyl ester (0.121 g, 0.200 mmole) and n-butyl bornic acid (0.061,0.600 mmole) to produce a colorless oil (0.046 g, 45%). Mass [EI+] 537(M+H)⁺.

Step B 2-(2-Butyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid

The titled compound was prepared using2-(2-Butyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid methyl ester (0.043 g, 0.080 mmole) to produce a colorless oil(0.033 g, 81%). Mass [EI+] 523 (M+H)⁺, [EI−] 521 (M−H)⁻.

Example 209 2-(4-{3-El-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-isobutyl-phenoxy)-2-methyl- propionic acid

Step A 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-isobutyl-phenoxy)-2-methyl- propionic acidmethyl ester

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionicacid methyl ester (0.121 g, 0.200 mmole) and isobutyl bornic acid(0.061, 0.600 mmole) to produce a colorless oil (0.089 g, 8.3%). Mass[EI+] 537 (M+H)⁺.

Step B 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-isobutyl-phenoxy)-2-methyl- propionic acid

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-isobutyl-phenoxy)-2-methyl-propionicacid methyl ester (0.088 g, 0.164 mmole) to produce colorless oil(0.0747 g, 87%). Mass [EI+] 523 (M+H)⁺, [EI−] 521 (M−H)⁻.

Example 210 2-(5-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-biphenyl-2-yloxy)-2-methyl- propionic acid

Step A 2-(5-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-biphenyl-2-yloxy)-2-methyl- propionic acidmethyl ester

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionicacid methyl ester (0.121 g, 0.200 mmole) and phenyl bornic acid (0.073,0.600 mmole) to produce a colorless oil (0.103 g, 93%). Mass [EI+] 557(M+H)⁺.

Step B 2-(5-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-biphenyl-2-yloxy)-2-methyl- propionic acid

The titled compound was prepared using 2-(5-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-biphenyl-2-yloxy)-2-methyl-propionicacid methyl ester (0.103 g, 0.185 mmole) to produce colorless oil(0.0967 g, 97%). Mass [EI+] 543 (M+H)⁺, [EI−] 541 (M−H)⁻.

Example 211 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl- propionic acid

Step A 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl- propionic acidmethyl ester

2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl- propionic acidmethyl ester (0.264 g, 0.435 mmole) and tributyl(vinyl) tin (0.207 g,0.652 mmole) were mixed in toluene (4.0 mL). After bubbled with nitrogenfor 15 minutes, tetrakis(triphenylphosphine) palladium(0) (0.050 g,0.043 mmole) was added. The reaction was heated at 80° C. overnight. Thesolvent was removed on rota-vapor, and the crude product was purified bycolumn chromatography (silica gel, gradient elution 0-30% acetone inhexane) to provide a colorless oil (0.158 g, 71%). Mass [EI+] 507(M+H)⁺.

Step B 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl- propionic acid

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl-propionicacid methyl ester (0.048 g, 0.094 mmole) to produce an oil (0.0445 g,95%). Mass [EI+] 493 (M+H)⁺, [EI−] 491 (M−H)⁻.

Example 212 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-ethyl-phenoxy)-2-methyl-propionic acid

Step A 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-ethyl-phenoxy)-2-methyl- propionic acidmethyl ester

2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl- propionic acidmethyl ester (0.110 g, 0.217 mmole) was dissolved in absolute ethanol (4mL). After purged the solution with N₂ for 15 min, 10% Pd/C (0.040 g).The reaction was stirred under a hydrogen balloon at room temperaturefor 2 hours. The catalyst was removed through filtration, and solventwas removed on rota-vapor to provide a colorless oil (0.110 g, 100%).Mass [EI+] 509 (M+H)⁺.

Step B 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-ethyl-phenoxy)-2-methyl- propionic acid

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-ethyl-phenoxy)-2-methyl-propionicacid methyl ester (0.110 g, 0.216 mmole) to produce an oil (0.0905 g,85%). Mass [EI+] 495 (M+H)⁺, [EI−] 493 (M−H)⁻.

Example 213 2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid

Step A 2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-ox,o-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-iodo-phenoxy)-2-methyl-propionicacid methyl ester (0.200 g, 0.330 mmole) and allyl tributyltin (0.218,0.659 mmole) to produce a colorless oil (0.102 g, 59%). Mass [EI+] 521(M+H)⁺.

Step B 2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid

The titled compound was prepared using2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl)-phenoxy)-2-methyl-propionicacid methyl ester (0.040 g, 0.076 mmole) to produce a colorless oil(0.027 g, 69%). Mass [EI+] 507 (M+H)⁺, [EI−] 508 (M−H)⁻.

Example 214 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-propyl-phenoxy)-2-methyl- propionic acid

Step A 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-propyl-phenoxy)-2-methyl- propionic acidmethyl ester

2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid methyl ester(0.060 g, 0.115 mmole) was dissolved in absolute ethanol (10 mL). Afterpurged the solution with N₂ for 15 min, 10% Pd/C (0.030 g). The reactionwas stirred under a hydrogen balloon at room temperature for 2 hours.The catalyst was removed through filtration, and solvent was removed onrota-vapor to provide a colorless oil (0.053 g, 88%). Mass [EI+] 523(M+H)⁺.

Step B 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-propyl-phenoxy)-2-methyl- propionic acid

The titled compound was prepared using 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-propyl-phenoxy)-2-methyl-propionicacid methyl ester (0.052 g, 0.100 mmole) to produce an oil (0.050 g,100%). Mass [EI+] 509 (M+H)⁺, [EI−] 507 (M−H)⁻.

Example 2152-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid

Step A 2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl- propionic acidmethyl ester

To a solution of2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionic acid (0.610 g, 1.27 mmole) in methanol (10 mL) was added 15drops of concentrated sulfuric acid. The mixture was stirred at roomtemperature overnight. After evaporated the solvent, the residue waspartitioned between ethyl acetate (50 mL) and water (50 mL). The organiclayer was washed by saturated sodium bicarbonate (50 mL), then brine(3×50 mL), dried over Na₂SO₄, filtered and concentrated in vacuo toproduce an oil (0.624 g, 99%). Mass [EI+] 495 (M+H)⁺.

Step B2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl ester

2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl- propionic acidmethyl ester (0.620 g, 1.25 mmole) was dissolved in 20% HOAc in EtOAC(50 mL). After purged the solution with N₂ for 15 min, 10% Pd/C (0.600g). The reaction was stirred under a hydrogen balloon at roomtemperature for overnight. The catalyst was removed through filtration,and solvent was removed on rota-vapor to provide a colorless oil (0.337g, 77%). Mass [EI+] 349 (M+H)⁺.

Step C2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid

The titled compound was prepared using2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl ester (0.112 g, 0.322 mmole) to produce an oil (0.054 g,50%). Mass [EI+] 335 (M+H)⁺, [EI−] 333 (M−H)⁻.

Example 2162-{4-[3-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-methyl-phenoxy}-2-methyl-propionicacid

The titled compound was prepared using2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl Ester (0.112 g, 0.322 mmole) and 4-phenyl benzyl chloride(0.078 g, 0.186 mmole) to produce an oil (0.054 g, 34%). Mass [EI+] 501(M+H)⁺, [EI−] 499 (M−H)⁻.

Example 2172-(4-{3-El-(4-Bromo-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionicacid

The titled compound was prepared using2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl Ester (0.100 g, 0.287 mmole) and 4-bromo benzyl bromide(0.108 g, 0.431 mmole) to produce an oil (0.058 g, 40%). Mass [EI+] 503,505 (M+H)⁺, [EI−] 501, 503 (M−H)⁻.

Example 2182-(4-{3-[1-(3-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionicacid

The titled compound was prepared using2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl Ester (0.100 g, 0.287 mmole) and 3-methoxy) benzyl bromide(0.087 g, 0.431 mmole) to produce an oil (0.042 g, 32%). Mass [EI+] 455(M+H)⁺, [EI−] 453 (M−H)⁻.

Example 2192-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid

The titled compound was prepared using2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl Ester (0.100 g, 0.287 mmole) and 2-chloromethyl-quinoline(0.092 g, 0.431 mmole) to produce an oil (0.023 g, 17%). Mass [EI+] 476(M+H)⁺, [EI-] 474 (M−H)⁻.

Example 2202-Methyl-2-{2-methyl-4-[3-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid

The titled compound was prepared using2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid methyl Ester (0.100 g, 0.287 mmole) and 2-Bromomethyl-naphthalene(0.095 g, 0.431 mmole) to produce an oil (0.080 g, 59%). Mass [EI+] 476(M+H)⁺, [EI−] 474 (M−H)⁻.

Example 2212-{4-[3-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-butyl-phenoxy}-2-methyl-propionicacid

Step A 2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl- propionic acidethyl ester

The titled compound was prepared using4-[3-(3-Butyl-4-hydroxy-phenyl)-propyl]-3-methyl-1-(4-trifluoromethyl-benzyl)-imidazolidin-2-one (0.210 g, 0.468 mmole) to produce an oil(0.258 g, 98%). Mass [EI+] 563 (M+H)⁺.

Step B 2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl- propionic acidethyl ester

The titled compound was prepared using2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid ethyl ester (0.215 g, 0.382 mmole) to produce an oil (0.049 g,32%). Mass [EI+] 405 (M+H)⁺.

Step C2-{4-[3-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-butyl-phenoxy}-2-methyl-propionicacid

The titled compound was prepared using2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid ethyl ester (0.049 g, 0.120 mmole) and 4-phenyl benzyl bromide(0.029 g, 0.144 mmole) to produce an oil (0.042 g, 65%). Mass [EI+] 543(M+H)⁺, [EI−] 541 (M−H)⁻.

Certain compounds of the present invention can be prepared using themethods illustrated by the following schemes:

Biological Assays Binding and Cotransfection Studies

The in vitro potency of compounds in modulating PPARγ and PPARαreceptors are determined by the procedures detailed below. DNA-dependentbinding (ABCD binding) is carried out using SPA technology with PPARreceptors. Tritium-labeled PPARα and PPARγ agonists are used asradioligands for generating displacement curves and IC₅₀ values withcompounds of the invention. Cotransfection assays are carried out inCV-1 cells. The reporter plasmid contained an acylCoA oxidase (AOX) PPREand TK promoter upstream of the luciferase reporter cDNA. AppropriatePPARs and RXRα are constitutively expressed using plasmids containingthe CMV promoter. For PPARα and PPARδ, interference by endogenous PPARγin CV-1 cells is an issue. In order to eliminate such interference, aGAL4 chimeric system is used in which the DNA binding domain of thetransfected PPAR is replaced by that of GAL4, and the GAL4 responseelement is utilized in place of the AOX PPRE. Cotransfection efficacy isdetermined relative to PPARα agonist and PPARγ agonist referencemolecules. Efficacies are determined by computer fit to aconcentration-response curve, or in some cases at a single highconcentration of agonist (10 μM). For binding or cotransfection studieswith receptors other than PPARs, similar assays are carried out usingappropriate ligands, receptors, reporter constructs, etc., for thatparticular receptor.

These studies are carried out to evaluate the ability of compounds ofthe invention to bind to and/or activate various nuclear transcriptionfactors, particularly huPPARγ (“hu” indicates “human”) and huPPARγ.These studies provide in vitro data concerning efficacy and selectivityof compounds of the invention. Furthermore, binding and cotransfectiondata for compounds of the invention are compared with corresponding datafor marketed compounds that act on either huPPARα or huPPARγ.

Binding and cotransfection data for representative compounds of theinvention are compared with corresponding data for reference todetermine the binding.

The binding and cotransfection efficacy values found, for compounds ofthe invention and compounds of this invention which are useful formodulating a PPAR alpha receptor, are ≦100 nM and ≧50%, respectively.When coagoanist modulators are desired, the values may be balancedagainst selectivity for the alpha, gamma, delta, or another desired PPARreceptor subtype.

Evaluation of Triglyceride Reduction and HDL Cholesterol Elevation inHuapoAI Transgenic Mice

Studies are performed to evaluate the effect of compounds of the presentinvention upon HDL and triglyceride levels in human apoAI mice. For eachcompound tested, seven to eight week old male mice, transgenic for humanapoAI (C57 BL/6-tgn(apoal)1rub, Jackson Laboratory, Bar Harbor, Me.) areacclimated in individual cages for two weeks with standard chow diet(Purina 5001) and water provided ad libitum. After the acclimation, miceand chow are weighed and assigned to test groups (n=5) withrandomization by body weight. Mice are dosed daily by oral gavage for 8days using a 29 gauge, 1-{fraction (1/2)} inch curved feeding needle(Popper & Sons). The vehicle for the controls, test compounds and thepositive control (fenofibrate 100 mg/kg) is 1% carboxymethylcellulose(w/v) with 0.25% tween 80 (w/v). All mice are dosed daily between 6 and8 a.m. with a dosing volume of 0.2 ml. Prior to termination, animals anddiets are weighed and body weight change and food consumption arecalculated. Three hours after last dose, mice are euthanized with CO₂and blood is removed (0.5-1.0 ml) by cardiac puncture. After sacrifice,the liver, heart, and epididymal fat pad are excised and weighed. Bloodis permitted to clot and serum is separated from the blood bycentrifugation.

Cholesterol and triglycerides are measured calorimetrically usingcommercially prepared reagents (for example, as available from Sigma#339-1000 and Roche #450061 for triglycerides and cholesterol,respectively). The procedures are modified from published work (McGowanM. W. et al., Clin Chem 29:538-542,1983; Allain C. C. et al., Clin Chem20:470-475,1974. Commercially available standards for triglycerides andtotal cholesterol, respectively, commercial quality control plasma, andsamples are measured in duplicate using 200 μl of reagent. An additionalaliquot of sample, added to a well containing 200 μl water, provides ablank for each specimen. Plates are incubated at room temperature on aplate shaker and absorbance is read at 500 nm and 540 nm for totalcholesterol and triglycerides, respectively. Values for the positivecontrol are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

Serum lipoproteins are separated and cholesterol quantitated by fastprotein liquid chromatography (FPLC) coupled to an in line detectionsystem. Samples are applied to a Superose 6 HR size exclusion column(Amersham Pharmacia Biotech) and eluted with phosphate bufferedsaline-EDTA at 0.5 ml/min. Cholesterol reagent (Roche DiagnosticsChol/HP 704036) at 0.16 ml/min is mixed with the column effluent througha T-connection and the mixture passed through a 15 m×0.5 mm id knittedtubing reactor immersed in a 37 C water bath. The colored productproduced in the presence of cholesterol is monitored in the flow streamat 505 nm and the analog voltage from the monitor is converted to adigital signal for collection and analysis. The change in voltagecorresponding to change in cholesterol concentration is plotted vs. timeand the area under the curve corresponding to the elution of very lowdensity lipoprotein (VLDL), low density lipoprotein (LDL) and highdensity lipoprotein (HDL) is calculated using Perkin Elmer Turbochromesoftware.

Triglyceride serum levels in mice dosed with a compound of the inventionare compared to mice receiving the vehicle to identify compounds whichcould be particularly useful for lowering triglycerides. Generally,triglyceride decreases of greater than or equal to 30% (thirty percent)compared to control following a 30 mg/kg dose suggests a compound thatcan be especially useful for lowering triglyceride levels.

The percent increase of HDLC serum levels in mice receiving a compoundof the invention is compared to mice receiving vehicle to identifycompounds of the invention that could be particularly useful forelevating HDL levels. Generally, and increase of greater than or equalto 25% (twenty five percent) increase in HDLc level following a 30 mg/kgdose suggests a compound that can be especially useful for elevatingHDLc levels.

It may be particularly desirable to select compounds of this inventionthat both lower triglyceride levels and increase HDLc levels. However,compounds that either lower triglyceride levels or increase HDLc levelsmay be desirable as well.

Evaluation of Glucose Levels in db/db Mice

The effects, upon plasma glucose of administering various dose levels ofdifferent compounds of the present invention is studied using thefollowing methods.

Five-week-old male diabetic (db/db) mice [for example,C57BlKs/j-m+/+Lepr(db), Jackson Laboratory, Bar Harbor, Me.] or leanlittermates are housed 6 per cage with food and water available at alltimes. After an acclimation period of 2 weeks, animals are individuallyidentified by ear notches, weighed, and bled via the tail vein fordetermination of initial glucose levels. Blood is collected (100 μl)from unfasted animals by wrapping each mouse in a towel, cutting the tipof the tail with a scalpel, and milking blood from the tail into aheparinized capillary tube. Sample is discharged into a heparinizedmicrotainer with gel separator and retained on ice. Plasma is obtainedafter centrifugation at 4° C. and glucose measured immediately.Remaining plasma is frozen until the completion of the experiment, whenglucose and triglycerides are assayed in all samples. Animals aregrouped based on initial glucose levels and body weights. Beginning thefollowing morning, mice are dosed daily by oral gavage for 7 days.Treatments are test compounds (30 mg/kg), a positive control agent (30mg/kg) or vehicle [1% carboxymethylcellulose (w/v)/0.25% Tween80 (w/v);0.3 ml/mouse]. On day 7, mice are weighed and bled (tail vein) 3 hoursafter dosing. Twenty-four hours after the 7^(th) dose (i.e., day 8),animals are bled again (tail vein). Samples obtained from consciousanimals on days 0, 7 and 8 are assayed for glucose. After the 24-hourbleed, animals are weighed and dosed for the final time. Three hoursafter dosing on day 8, animals are anesthetized by inhalation ofisoflurane and blood obtained via cardiac puncture (0.5-0.7 ml). Wholeblood is transferred to serum separator tubes, chilled on ice andpermitted to clot. Serum is obtained after centrifugation at 4° C. andfrozen until analysis for compound levels. After sacrifice by cervicaldislocation, the liver, heart and epididymal fat pads are excised andweighed.

Glucose is measured calorimetrically using commercially purchasedreagents. According to the manufacturers, the procedures are modifiedfrom published work (McGowan, M. W., Artiss, J. D., Strandbergh, D. R. &Zak, B. Clin Chem, 20:470-5 (1974) and Keston, A. Specific colorimetricenzymatic analytical reagents for glucose. Abstract of papers 129thMeeting ACS, 31C (1956).); and depend on the release of a mole ofhydrogen peroxide for each mole of analyte, coupled with a colorreaction first described by Trinder (Trinder, P. Determination ofglucose in blood using glucose oxidase with an alternative oxygenacceptor. Ann Clin Biochem, 6:24 (1969)). The absorbance of the dyeproduced is linearly related to the analyte in the sample. The assayswere further modified in our laboratory for use in a 96 well format. Thecommercially available standard for glucose, commercially availablequality control plasma, and samples (2 or 5 μl/well) are measured induplicate using 200 μl of reagent. An additional aliquot of sample,pipetted to a third well and diluted in 200 μl water, provides a blankfor each specimen. Plates are incubated at room temperature for 18minutes for glucose on a plate shaker (DPC Micormix 5) and absorbance isread at 500 nm on a plate reader. Sample absorbances are compared to astandard curve (100-800 for glucose). Values for the quality controlsample are always within the expected range and the coefficient ofvariation for samples is below 10%. All samples from an experiment areassayed at the same time to minimize inter-assay variability.

Evaluation of the Effects of Compounds of the Present Invention uponA^(Y) Mice Body Weight, Fat Mass, Glucose and Insulin Levels

Female A^(y) Mice

Female A^(Y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty weeks ofage the mice are randomly assigned to vehicle control and treated groupsbased on body weight and body fat content as assessed by DEXA scanning(N=6). Mice are then dosed via oral gavage with either vehicle or aCompound of this invention (50 mg/kg) one hour after the initiation ofthe light cycle (for example, about 7 A.M.) for 18 days. Body weightsare measured daily throughout the study. On day 14 mice are maintainedin individual metabolic chambers for indirect calorimetry assessment ofenergy expenditure and fuel utilization. On day 18 mice are againsubjected to DEXA scanning for post treatment measurement of bodycomposition.

The results of p.o. dosing of compound for 18 days on body weight, fatmass, and lean mass are evaluated and suggest which compounds of thisinvention can be especially useful for maintaining desirable weightand/or promoting desired lean to fat mass.

Indirect calorimetry measurements reveal a significant reduction inrespiratory quotient (RQ) in treated animals during the dark cycle[0.864±0.013 (Control) vs. 0.803±0.007 (Treated); p<0.001]. Thisreduction in RQ is indicative of an increased utilization of fat duringthe animals' active (dark) cycle. Additionally, treated animals displaysignificantly higher rates of energy expenditure than control animals.

Male KK/A^(y) Mice

Male KK/A^(y) mice are singly housed, maintained under standardizedconditions (22° C., 12 h light:dark cycle), and provided free access tofood and water throughout the duration of the study. At twenty-two weeksof age the mice are randomly assigned to vehicle control and treatedgroups based on plasma glucose levels. Mice are then dosed via oralgavage with either vehicle or a Compound of this invention (30 mg/kg)one hour after the initiation of the light cycle (7 A.M.) for 14 days.Plasma glucose, triglyceride, and insulin levels are assessed on day 14.

The results of p.o. dosing of compound for 14 days on plasma glucose,triglycerides, and insulin are evaluated to identify compounds of thisinvention which may be especially desired.

Method to Elucidate the LDL-Cholesterol Total-Cholesterol andTriglyceride Lowering Effect

Male Syrian hamsters (Harlan Sprague Dawley) weighing 80-120 g areplaced on a high-fat cholesterol-rich diet for two to three weeks priorto use. Feed and water are provided ad libitum throughout the course ofthe experiment. Under these conditions, hamsters becomehypercholesterolemic showing plasma cholesterol levels between 180-280mg/dl. (Hamsters fed with normal chow have a total plasma cholesterollevel between 100-150 mg/dl.) Hamsters with high plasma cholesterol (180mg/dl and above) are randomized into treatment groups based on theirtotal cholesterol level using the GroupOptimizeV211.xls program.

A Compound of this invention is dissolved in an aqueous vehicle(containing CMC with Tween 80) such that each hamster receives once aday approx. 1 ml of the solution by gavage at doses 3 and 30 mg/kg bodyweight. The blank control is vehicle alone. Dosing is performed daily inthe early morning for 14 days.

Quantification of Plasma Lipids:

On the last day of the test, hamsters are bled (400 ul) from thesuborbital sinus while under isoflurane anesthesia 2 h after dosing.Blood samples are collected into heparinized microfuge tubes chilled inice bath. Plasma samples are separated from the blood cells by briefcentrifugation. Total cholesterol and triglycerides are determined bymeans of enzymatic assays carried out automatically in the Monarchequipment (Instrumentation Laboratory) following the manufacturer'sprocedure. Plasma lipoproteins (VLDL, LDL and HDL) are resolved byinjecting 25 ul of the pooled plasma samples into an FPLC system elutedwith phosphate buffered saline at 0.5 ml/min through a Superose 6 HR10/30 column (Pharmacia) maintained room temp. Detection andcharacterization of the isolated plasma lipids are accomplished bypostcolumn incubation of the effluent with a Cholesterol/HP reagent (forexample, Roche Lab System; infused at 0.12 ml/min) in a knitted reactioncoil maintained at 37° C. The intensity of the color formed isproportional to the cholesterol concentration and is measuredphotometrically at 505 nm.

The effect of administration of a Compound of this invention for 14 daysis studied for the percent reduction in LDL level with reference to thevehicle group. The LDL- lowering efficacy for certain compounds of thisinvention can be especially desired. Compounds of this invention thatdecrease LDL greater than or equal to 30% (thirty percent) compared tovehicle can be especially desired.

The total-cholesterol and triglyceride lowering effects of a Compound ofthis invention are also studied. The data for reduction in totalcholesterol and triglyceride levels after treatment with a compound ofthis invention for 14 days is compared to the vehicle to suggestcompounds that can be particularly desired.

Method to Elucidate the Fibrinogen-Lowering Effect of PPAR Modulators

Zucker Fatty Rat Model:

The life phase of the study on fibrinogen-lowering effect of compoundsof this invention is part of the life phase procedures for theantidiabetic studies of the same compounds. On the last (14^(th)) day ofthe treatment period, with the animals placed under surgical anesthesia,˜3 ml of blood is collected, by cardiac puncture, into a syringecontaining citrate buffer. The blood sample is chilled and centrifugedat 4° C. to isolate the plasma that is stored at −70° C. prior tofibrinogen assay.

Quantification of Rat Plasma Fibrinogen:

Rat plasma fibrinogen levels are quantified by using a commercial assaysystem consists of a coagulation instrument following the manufacturer'sprotocol. In essence, 100 ul of plasma is sampled from each specimen anda 1/20 dilution is prepared with buffer. The diluted plasma is incubatedat 37° C. for 240 seconds. Fifty microliters of clotting reagentthrombin solution (provided by the instrument's manufacturer in astandard concentration) is then added. The instrument monitors theclotting time, a function of fibrinogen concentration quantified withreference to standard samples.

Results:

Compounds of this invention may lowering fibrinogen level in vivo.Compounds that lower fibrinogen level greater than vehicle can beespecially desired.

Method to Elucidate the Anti-Body Weight Gain and Anti- Appetite Effectsof Compounds of This Invention

Fourteen-Day Study in Zucker Fatty Rat¹ or ZDF Rat² Models:

Male Zucker Fatty rats, non-diabetic (Charles River Laboratories,Wilmington, Mass.) or male ZDF rats (Genetic Models, Inc, Indianapolis,Ind.) of comparable age and weight are acclimated for 1 week prior totreatment. Rats are on normal chow and water is provided ad libitumthroughout the course of the experiment.

Compounds of this invention are dissolved in an aqueous vehicle suchthat each rat receives once a day approximately 1 ml of the solution bygavage at doses 0.1, 0.3, 1 and 3 mg/kg body weight. Fenofibrate (SigmaChemical, prepared as a suspension in the same vehicle) a knownalpha-agonist given at doses of 300 mg/kg, as well as the vehicle arecontrols. Dosing is performed daily in the early morning for 14 days.Over the course of the experiment, body weight and food consumption aremonitored.

Using this assay, compounds of this invention are found to result insignificant weight reduction.

EQUIVALENTS

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims.

1. A Compound of the structural Formula I,

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: (a) R1 is selected from the group consisting of hydrogen,substituted or unsubstituted group selected from C₁-C₈ alkyl,aryl-C₀₋₄-alkyl, heteroaryl- C₀₋₄-alkyl, C₃-C₆cycloalkylaryl-C₀₋₂-alkyl, and —CH₂—C(O)—R17-R18, wherein R17 is O or NHand R18 is optionally substituted benzyl; (b) R2 is H or a substitutedor unsubstituted group selected from the group consisting of C₁-C₆alkyl, C₁-C₆ alkenyl, aryl-C₀₋₄-alkyl, heteroaryl-C₀₋₄-alkyl, C₁-C₄alkyl sulfonamide, C₁-C₄ alkyl amide, OR10 and C₃-C₆ cycloalkyl; (c) WisO or S; (d) X is an optionally substituted C₁-C₅ alkylene linker whereinone carbon atom of the linker may optionally be replaced with O, NH, S,and optionally two carbons together may form a double bond; (e) Y isselected from the group consisting of C, O, S, NH and a single bond; and(f) E is selected from the group consisting of C(R3)(R4)A, A, and asubstituted or unsubstituted group selected from the group consisting of(CH₂)_(n) COOR19; and wherein (i) n is 0, 1, 2 or 3; (ii) A is anfunctional group selected from the group consisting of carboxyl,C₁-C₃alkylnitrile, carboxamide, substituted or unsubstitutedsulfonamide, substituted or unsubstituted acylsulfonamide substituted orunsubstituted tetrazole, and substituted or unsubstituted isoxazole;(iii) R3 is selected from the group consisting of H, C₁-C₅ alkyl, andC₁-C₅ alkoxy, and (iv) R4 is selected from the group consisting of H,halo, and a substituted or unsubstituted group selected from C₁-C₅alkyl, C₁-C₅ alkoxy, C₃-C₆ cycloalkyl, aryl C₀-C₄ alkyl, arylC₀-C₂alkoxyand phenyl; or R3 and R4 are combined to form a C₃-C₈ cycloalkyl; (v)R19 is selected from the group consisting of hydrogen, optionallysubstituted arylmethyl and optionally substituted C₁-C₄alkyl; (g) R8 isselected from the group consisting of hydrogen, C₁-C₄ alkyl, C₁-C₄alkenyl, and halo; (h) R9 is selected from the group consisting ofhydrogen, C₁-C₄ alkyl, C₁-C₄ alkenyl, halo, substituted or unsubstitutedaryl, substituted or unsubstituted aryl-C₁-C₄ alkyl, substituted orunsubstituted heteroaryl, C₁-C₆ alkenyl, and OR10; (i) R10 isindependently selected from the group consisting of hydrogen and C₁-C₄alkyl; (j) R21 is selected from the group consisting of hydrogen, ═O,and a substituted or unsubstituted group selected from the groupconsisting of C₁-C₆ alkyl, aryl, C₁-C₄ alkylaryl, and heteroaryl; (k)R22 is selected from the group consisting of hydrogen, and a substitutedor unsubstituted group selected from the group consisting of C₁-C₆alkyl, aryl, C₁-C₄ alkylaryl, and heteroaryl; and (k) ----represents anoptional double bond.
 2. (Cancelled).
 3. A compound as claimed by claim1 that is represented by the following structural formula:

and salts, solvates and hydrates thereof.
 4. A compound as claimed byclaim 1 that is represented by the following structural formula:

and salts, solvates and hydrates thereof.
 5. A compound as claimed byclaim 3 wherein W is O.
 6. A compound as claimed by claim 3 wherein E isA.
 7. A compound as claimed by claims 3 wherein A is COOH.
 8. A compoundas claimed by claim 3 wherein Y is O.
 9. A compound as claimed by claims3 wherein Y is C.
 10. A compound as claimed by claim 3 wherein E isC(R3)(R4)A.
 11. A compound as claimed by claim 4 wherein E is a group ofthe formula:

wherein R14 is selected from the group consisting of H, CF₃, substitutedor unsubstituted phenyl, substituted or unsubstituted aryl-C₀₋₄-alkyl,and C₁₋₆-alkyl.
 12. A compound as claimed by claim 8 wherein E is agroup of the formula:

wherein R17 is selected from the group consisting of H, and C₁₋₆-alkyl.13. A compound as claimed by claim 1 wherein X is optionally substitutedC₂-C₅ alkylene.
 14. A compound as claimed by claims 1 wherein X ispropylene.
 15. A compound as claimed by claim 8 wherein the E-Y group isin the para position in relation to the X linker.
 16. A compound asclaimed by claim 8 wherein R2 is C₁-C₂ alkyl.
 17. A compound as claimedby claim 3 wherein R1 is substituted benzyl.
 18. A compound as claimedby claims 17 wherein R1 is substituted benzyl wherein the benzylsubstituent is one or two independently selected from the groupconsisting of CF₃, C₁-C₄ alkyl, and halo.
 19. A compound as claimed byclaim 18 wherein R1 is substituted benzyl wherein there is one parasubstituted benzyl substituent on the benzyl ring.
 20. A compound asclaimed by claims 1 or 3 wherein X is C₁-C₃alkyl-O—.
 21. A compound asclaimed by claims 10 wherein R4 is aryloxy.
 22. A compound as claimed byclaim 1 that is represented by the following structural formula:

wherein (a) LI is O or CH₂; (b) V is a bond or a unsubstituted orsubstituted C₁-C₃ alkylene group; (c) R5 is substituted or unsubstitutedgroup selected from the group consisting of aryl, heteroaryl andcycloalkyl groups; and (d) salts, solvates and hydrates thereof.
 23. Acompound as claimed by claim 3 wherein R4 has S stereochemistry inrelation to R3.
 24. A compound as claimed by claim 1 represented by thefollowing structural Formula:

and salts, solvates and hydrates thereof.
 25. A compound as claimed byclaim 20 represented by the following structural formula:

wherein Q is C, O or S; and salts, solvates and hydrates thereof.
 26. Acompound as claimed by claim 20 represented by the following structuralformula:

wherein Q is C, O or S; and salts, solvates and hydrates thereof.
 27. Acompound as claimed by claim 26 that is represented by the followingstructural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: (a) X is an optionally substituted C₁-C₅ alkylene linkerwherein one carbon atom of the linker may be replaced with O, NH or S;(b) R3 is H, C₁-C₅ alkyl, or C₁-C₅ alkoxy; (c) R4 is H, halo, asubstituted or unsubstituted group selected from C₁-C₅ alkyl, C₁-C₅alkoxy, aryloxy, C₃-C₆ cycloalkyl and phenyl, or R3 and R4 are combinedto form a C₃-C₈ cycloalkyl; (d) V is a bond or a unsubstituted orsubstituted C₁-C₃ alkylene group; and (e) R5 is.substituted orunsubstituted group selected from the group consisting of aryl,heteroaryl, and cycloalkyl groups.
 28. A compound as claimed by claim 27that is represented by the following structural formula:

and pharmaceutically acceptable salts, solvates and hydrates thereof,wherein: (a) X is an optionally substituted C₁-C₅ alkylene linkerwherein one carbon atom of the linker may be replaced with O, NH or S;(b) R3 is H, C₁-C₅ alkyl, or C₁-C₅ alkoxy; (c) V is a bond or aunsubstituted or substituted C₁-C₃ alkylene group; and (d) R5 issubstituted or unsubstituted group.selected from the group consisting ofaryl, heteroaryl and cycloalkyl groups.
 29. A compound as claimed byclaim 28 that is represented by the following structural formula:

and salts, solvates, and hydrates thereof; wherein (a) R3 is H or C₁-C₅alkyl; (b) V is a bond or a unsubstituted or substituted C₁-C₃ alkylenegroup; (c) R5 is substituted or unsubstituted group selected from thegroup consisting of aryl, heteroaryl and cycloalkyl groups.
 30. Acompound as claimed by claim 27 that is represented by the followingstructural formula:

wherein: (a) R3 is H or C₁-C₅ alkyl; (b) V is a bond or a unsubstitutedor substituted C₁-C₃ alkylene group; (c) R5 is substituted orunsubstituted group selected from the group consisting of aryl,heteroaryl and cycloalkyl groups; and (d) salts, solvates and hydratesthereof.
 31. A Compound as claimed by claim 1 that is represented by thefollowing structural formula:

and salts, solvates and hydrates thereof.
 32. A compound as claimed byclaim 4 that is2-methyl-3-(4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenyl)-2-phenoxy-propionicacid or 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid.
 33. Apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and at least one compound as claimed by any one of claims 1 or2, or a pharmaceutically acceptable salt, solvate or hydrate thereof.34. A method of modulating a peroxisome proliferator activated receptor,comprising the step of contacting the receptor with at least onecompound as claimed by claim 2, or a pharmaceutically acceptable salt,solvate or hydrate thereof.
 35. A method of treating diabetes mellitusin a mammal, comprising the step of administering to the mammal in needthereof, a therapeutically effective amount of at least one compound ofclaim 2, or a pharmaceutically acceptable salt, solvate or hydratethereof.
 36. A method of preventing diabetes mellitus in a mammal,comprising the step of administering to the mammal in need thereof, apharmaceutically effective amount of at least one compound of claim 1,or a pharmaceutically acceptable salt, solvate or hydrate thereof.
 37. Amethod of treating Syndrome X in a mammal, comprising the step ofadministering to the mammal in need thereof, a therapeutically effectiveamount of at least one compound of claim 1, or a pharmaceuticallyacceptable salt, solvate or hydrate thereof.
 38. A method of treatingcardiovascular disease in a mammal, comprising the step of administeringto the mammal in need thereof, a therapeutically effective amount of atleast one compound of claims 1 or 2, or a pharmaceuticallyacceptable.salt, solvate or hydrate thereof.
 39. (Cancelled) 40.(Cancelled)
 41. (Cancelled)
 42. A compound of claim 1 selected from thegroup consisting of:2-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-2-methyl-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoky)-2-methyl-propionicacid;1-(4-tert-Butyl-benzyl)-4-[3-(4-methoxy-3-methyl-phenyl)-2-(2-Butyl-4-{3-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-3-(4-{12-[3-methyl-2-oxo-1-(3-phenoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid; 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid;2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid;2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methylester;2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid;3-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid;3-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionic acid;2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid;3-(4-{2-[1-(4-Chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionic acid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid;3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(2-fluoro-phenoxy)-2-methyl-propionicacid2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid; 2-(2-Fluoro-phenoxy)-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionic acid ethyl ester;3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid;2-Butoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid;2-Butoxy-3-(4-{2-[1-(4-chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid;2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Butoxy-3-(4-{2-[1-(4-chloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid;2-Butoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid;2-Ethoxy-3-(4-{2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid;2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-propoxy-propionicacid;2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Ethoxy-3-(4-{2-[1-(3-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-propionicacid;2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;3-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-ethoxy-2-methyl-propionicacid;3-(4-{2-[1-(3,4-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid;2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Ethoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid;3-(4-{2-[3-Ethyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionicacid; 3-(4-{2-[3-(2-Methoxy-ethyl)-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-phenoxy-propionic acid;2-Butoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;3-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid;3-{4-[2-(1-Benzyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-butoxy-2-methyl-propionicacid;2-Methoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Methoxy-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionic acid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid; 2,2-Dimethyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl-ethoxy]-phenyl}-propionic acid;2-methyl-3-{4-[2-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionicacid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethyl-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid;3-(4-{0.2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;2-(4-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid;3-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(4-fluoro-phenoxy)-2-methyl-propionicacid;3-(4-{2-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid;2-Methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-(4-trifluoromethyl-phenoxy)-propionicacid;3-(4-{2-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-methyl-2-(4-trifluoromethyl-phenoxy)-propionicacid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-phenoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionicacid; 2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid;2-Methyl-3-(4-{2-[3-methyl-2-oxo-1-(3-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-{2-[3-methyl-2-oxo-1-(4-trifluoromethoxy-benzyl)-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid;2-(2-Fluoro-phenoxy)-2-methyl-3-(4-2-[3-methyl-1-(4-methyl-benzyl)-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-propionicacid;3-(4-{2-[1-(3,4-Dichloro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid;3-(4-{2-[1-(3,4-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid;3-(4-{2-[1-(3,5-Difluoro-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethoxy}-phenyl)-2-(2-fluoro-phenoxy)-2-methyl-propionicacid;2-(2-Fluoro-phenoxy)-2-methyl-3-{4-[2-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-propionicacid; 3-{4-[2-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-methyl-2-phenoxy-propionicacid;2-(2-Butyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-isobutyl-phenoxy)-2-methyl-propionicacid;2-(5-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-biphenyl-2-yloxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-ethyl-phenoxy)-2-methyl-propionicacid;2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-propyl-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid; 2-{4-[3-(11-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-methyl-phenoxy}-2-methyl-propionicacid;2-(4-{3-[1-(4-Bromo-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(3-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionicacid; 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid;2-Methyl-2-{2-methyl-4-[3-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid;2-{4-[3-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-butyl-phenoxy}-2-methyl-propionicacid;2-(2-Butyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-isobutyl-phenoxy)-2-methyl-propionicacid;2-(5-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-biphenyl-2-yloxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-vinyl-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-ethyl-phenoxy)-2-methyl-propionicacid;2-(2-Allyl-4-{3-[1-(4-tert-butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-propyl-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionicacid;2-{4-[3-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-methyl-phenoxy}-2-methyl-propionicacid;2-(4-{3-[1-(4-Bromo-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(3-Methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-propyl}-2-methyl-phenoxy)-2-methyl-propionicacid; 2-Methyl-2-{2-methyl-4-[3-(3-methyl-2-oxo-1-quinolin-2-ylmethyl-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid;2-Methyl-2-{2-methyl-4-[3-(3-methyl-1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid;2-{4-[3-(1-Biphenyl-4-ylmethyl-3-methyl-2-oxo-imidazolidin-4-yl)-propyl]-2-butyl-phenoxy}-2-methyl-propionicacid; and a compound of the formula:


43. A compound of claim 1, selected from the group consisting of:2-(4-{3-[1-(4-tert-Butyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(3-Methoxy-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{4-[3-(2-oxo-1-quinolin-2-ylmethyl-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-propioriicacid;2-Methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-propionicacid;2-(4-{3-[1-(3,5-Difluoro-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-{4-[3-(1-Benzyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-2-methyl-propionicacid; 2-Methyl-2-{4-[3-(1-naphthalen-2-ylmethyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-propionic acid;2-Methyl-2-{4-[3-(2-oxo-1-phenethyl-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-propionic acid;2-(4-{3-[1-(4-Isopropyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-Ethyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-{4-[3-(1,3-Dibenzyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-2-methyl-propionicacid; 2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-3-ethyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-tert-Butyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(3-Methoxy-benzy)-2-oxo-3popyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-2-(4-{3-[3-methyl-1-(4-methyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-propionic acid;2-Methyl-2-{4-[3-(2-oxo-3-propyl-1-quinolin-2-ylmethyl-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-propionic acid;2-Methyl-2-(4-{3-[1-(4-methyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-propionic acid;2-(4-{3-[3-Hexyl-1-(4-methyl-benzyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{4-[3-(1-naphthalen-2-ylmethyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-propionicacid; 2-(4-{3-[1-(3,5-Difluoro-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[3-Cyclopropylmethyl-1-(3,5-difluoro-benzyl)-2-oxo-2,3-dihydro-1-H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-{4-[3-(1-Benzyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-2-methyl-propionicacid;2-(4-{3-[1-(3,4-Dimethyl-benzyl)-3-(2-methoxy-ethyl)-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid; 2-(4-{3-[1-(3,4-Dimethyl-benzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(3-Chloro-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid; 2-(4-{3-[1-(3,4-Difluoro-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(3,4-Dichloro-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(4-Fluoro-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(3,5-Bis-trifluoromethyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{4-[3-(2-oxo-1-phenethyl-3-propyl-2,3-dihydro-1H-imidazol-4-yl)-propyl]-phenoxy}-propionicacid;2-(4-{3-[1-(4-Isopropyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-Ethyl-benzyl)-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[3-(3,4-Dimethyl-benzyl)-2-oxo-3-pyridin-4-ylmethyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid; 2-(4-{3-[3-(3,4-Dimethyl-benzyl)-2-oxo-1-propyl-2,3-dihydro-1H-imidazol-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{4-[3-(1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid;2-(4-{3-[1-(3,4-Dimethyl-benzyl)-2,5-dioxo-3-propyl-imidazolidin-4-yl]-propyl-phenoxy}-2-methyl-propionic acid;2-(4-{3-[3-(4-Methoxy-benzyl)-1-naphthalen-2-ylmethyl-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(3,5-Difluoro-benzyl)-4-methyl-2,5-dioxo-3-propyl-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(3,4-Dimethyl-benzyl)-4-methyl-2,5-dioxo-3-propyl-imidazolidin⁻⁴-yl]-propyl}-phenoxy)-2-methyl-propionic acid;2-(4-{3-[1-(3,4-Dimethyl-benzyl)-4-methyl-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-(4-{3-[1-(4-Ethyl-benzyl)-4-methyl-2,5-dioxo-imidazolidin-4-yl]-propyl}-phenoxy)-2-methyl-propionicacid;2-Methyl-2-{4-[3-(1-naphthalen-2-ylmethyl-2-oxo-imidazolidin-4-yl)-propyl]-phenoxy}-propionic acid; and2-{4-[2-(1,3-Dibenzyl-2,5-dioxo-imidazolidin-4-yloxy)-ethyl]-phenoxy}-2-methyl-propionicacid.